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Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review

Published:October 26, 2021DOI:https://doi.org/10.1016/j.cmi.2021.10.005

      Abstract

      Background

      Vaccines are critical cost-effective tools to control the coronavirus disease 2019 (COVID-19) pandemic. However, the emergence of variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may threaten the global impact of mass vaccination campaigns.

      Aims

      The objective of this study was to provide an up-to-date comparative analysis of the characteristics, adverse events, efficacy, effectiveness and impact of the variants of concern for 19 COVID-19 vaccines.

      Sources

      References for this review were identified through searches of PubMed, Google Scholar, BioRxiv, MedRxiv, regulatory drug agencies and pharmaceutical companies' websites up to 22nd September 2021.

      Content

      Overall, all COVID-19 vaccines had a high efficacy against the original strain and the variants of concern, and were well tolerated. BNT162b2, mRNA-1273 and Sputnik V after two doses had the highest efficacy (>90%) in preventing symptomatic cases in phase III trials. mRNA vaccines, AZD1222, and CoronaVac were effective in preventing symptomatic COVID-19 and severe infections against Alpha, Beta, Gamma or Delta variants. Regarding observational real-life data, full immunization with mRNA vaccines and AZD1222 seems to effectively prevent SARS-CoV-2 infection against the original strain and Alpha and Beta variants but with reduced effectiveness against the Delta strain. A decline in infection protection was observed at 6 months for BNT162b2 and AZD1222. Serious adverse event rates were rare for mRNA vaccines—anaphylaxis 2.5–4.7 cases per million doses, myocarditis 3.5 cases per million doses—and were similarly rare for all other vaccines. Prices for the different vaccines varied from $2.15 to $29.75 per dose.

      Implications

      All vaccines appear to be safe and effective tools to prevent severe COVID-19, hospitalization, and death against all variants of concern, but the quality of evidence greatly varies depending on the vaccines considered. Questions remain regarding a booster dose and waning immunity, the duration of immunity, and heterologous vaccination. The benefits of COVID-19 vaccination outweigh the risks, despite rare serious adverse effects.

      Keywords

      Background

      The implementation of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major asset in slowing down the coronavirus disease 2019 (COVID-19) pandemic. At the time of writing, more than 100 vaccines have been developed, and 26 vaccines have been evaluated in phase III clinical trials, according to the World Health Organization (WHO) [
      • World Health Organization
      Draft landscape and tracker of COVID-19 candidate vaccines.
      ].
      Recently, several variants of concern (VOCs) have emerged, including Alpha (known as 501Y.V1 with GISAID nomenclature or B.1.1.7 variant with PANGO nomenclature), Beta (501Y.V2 or B.1.351), Gamma (501Y.V3 or P1) and Delta (G/478K.V1 or B.1.617.2). These variants have been associated with an increase in the transmission or mortality of COVID-19 [
      • Volz E.
      • Mishra S.
      • Chand M.
      • Barrett J.C.
      • Johnson R.
      • Geidelberg L.
      • et al.
      Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England.
      ,
      • Coutinho R.M.
      • Marquitti F.M.D.
      • Ferreira L.S.
      • Borges M.E.
      • Silva RLP da
      • Canton O.
      • et al.
      Model-based estimation of transmissibility and reinfection of SARS-CoV-2 P.1 variant.
      ,
      • Davies N.G.
      • Jarvis C.I.
      • Edmunds W.J.
      • Jewell N.P.
      • Diaz-Ordaz K.
      • Keogh R.H.
      Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7.
      ,
      • Challen R.
      • Brooks-Pollock E.
      • Read J.M.
      • Dyson L.
      • Tsaneva-Atanasova K.
      • Danon L.
      Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study.
      ,
      • Faria N.R.
      • Mellan T.A.
      • Whittaker C.
      • Claro I.M.
      • Candido D. da S.
      • Mishra S.
      • et al.
      Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil.
      ] or may escape immunity when compared to the original strain or D614G variant [
      • Planas D.
      • Bruel T.
      • Grzelak L.
      • Guivel-Benhassine F.
      • Staropoli I.
      • Porrot F.
      • et al.
      Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies.
      ,
      • Edara V.V.
      • Hudson W.H.
      • Xie X.
      • Ahmed R.
      • Suthar M.S.
      Neutralizing antibodies against SARS-CoV-2 variants after infection and vaccination.
      ,
      • Wang P.
      • Nair M.S.
      • Liu L.
      • Iketani S.
      • Luo Y.
      • Guo Y.
      • et al.
      Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.
      ,
      • Cele S.
      • Gazy I.
      • Jackson L.
      • Hwa S.-H.
      • Tegally H.
      • Lustig G.
      • et al.
      Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma.
      ,
      • Wibmer C.K.
      • Ayres F.
      • Hermanus T.
      • Madzivhandila M.
      • Kgagudi P.
      • Oosthuysen B.
      • et al.
      SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma.
      ].
      While phase III trials assess the efficacy under controlled conditions, phase IV studies evaluate the real-world effectiveness of the vaccines in an observational design among a larger general population. These studies bring crucial information about rare or long-term effects, the prevention of asymptomatic infection, and the severity of COVID-19.
      The administration of COVID-19 vaccines is a major priority for many countries around the world. Due to the speed of production of scientific data in the context of this pandemic, it can be difficult for healthcare professionals to update themselves on the latest data concerning COVID-19 vaccines.
      The objective of this review is to provide an up-to-date comparative analysis of the characteristics, adverse events, efficacy, effectiveness, and impact of the variants of concern on the following 19 COVID-19 vaccines: mRNA vaccines (BNT16b2, mRNA-1273, CVnCoV), viral vector vaccines (AZD1222, Sputnik V, Sputnik V Light, Ad5-nCoV (Convidecia), Ad26.COV2.S), inactivated vaccines (NVX-COV2373, CoronaVac, BBIBP-CorV, Wuhan Sinopharm inactivated vaccine, Covaxin, QazVac, KoviVac, COVIran Barekat), and protein-based vaccines (EpiVacCorona, ZF2001, Abdala).

      Methods

      Electronic searches for studies were conducted using Pubmed and Google scholar until 22nd September 2021 using the search terms “SARS-CoV-2”, “COVID-19”, “efficacy”, “effectiveness”, “neutralization assays”, and “neutralization antibodies” in addition to the scientific or commercial names of the vaccines reported by WHO in phase III/IV. The ClinicalTrials.gov database was consulted using the terms “COVID-19” and “vaccine”. BioRxiv and MedRxiv, regulatory drug agencies and pharmaceutical companies' websites were also consulted for unpublished results and additional information. Vaccines included in this review were approved in at least one country. CVnCoV and NVX-CoV2373 were in rolling review by the European Medicine Agency (EMA) and were included in this review.
      Efficacy refers to the degree to which a vaccine prevents symptomatic or asymptomatic infection under controlled circumstances such as clinical trials. Effectiveness refers to how well the vaccine performs in the real world. In clinical trials, the main endpoint was the prevention of symptomatic COVID-19, whereas in observational studies endpoints were various and included asymptomatic SARS-CoV-2 infection, COVID-19, hospitalization or mortality.
      Regarding seroneutralization assays, we extracted the age of the study population, dosage, and fold decrease in geometric mean titre for 50% neutralization compared to the SARS-CoV-2 reference strain for each vaccine and each SARS-CoV-2 variant when it was available.

      Evidence on vaccine efficacy and effectiveness

      At the time of this review, 17 vaccines have been authorized in at least one country (Supplementary Material Table S1) and two vaccines (CVnCoV and NVX-CoV2373) are under evaluation.
      We briefly compared the COVID-19 vaccines schedule, type of vaccine, manufacturer, dosage, conditions of use/storage/transport, composition and price (Table 1). The main results of phase III clinical trials for each vaccine are described in Table 2 and in Fig. 1). Characteristics of SARS-CoV-2 variants (Alpha, Beta, Gamma, Epsilon, Eta, Zeta, Iota, Kappa and Delta) are described in Table 3. The results of observational real-world studies are specified in Fig. 2, Fig. 3, Fig. 4 and in the Supplementary Material Table S2. Seroneutralization assay results are summarized in Fig. 5 using boxplots per vaccine and per variant, and Supplementary Material Table S3 describes the 54 studies in detail.
      Table 1Characteristics of coronavirus disease 2019 (COVID-19) vaccines
      VaccineManufacturerType of vaccineDoseInjection dose interval in the phase III trialCondition of use/storageCompositionCost for one dose
      BNT16b2Pfizer/BioNtechRNA-based30 μg

      5–7-dose vial

      0.3 mL per dose
      Intramuscularly

      2 doses 21 days apart
      Supplied as a frozen vial

      The withdrawal of 6–7 doses from a single vial is dependent, in part, on the type of syringes and needles used to withdraw doses from the vials

      The vaccine must be diluted

      Frozen vials prior to use can be stored before dilution: –80°C to –60°C up to the end of its expiry date or at –25°C to –15°C for up to 2 weeks

      Vials prior to dilution may be stored at +2°C to +8°C for up to 31 days or may be at room temperature up to +25°C for no more than 2 hours prior to use, or can be thawed in the refrigerator for 2–3 hours or at room temperature (up to +25°C) for 30 minutes

      After dilution: +2°C to +25°C

      Has to be used within 6 hours from the time of dilution
      A synthetic messenger ribonucleic acid (mRNA) encoding the spike protein of SARS-CoV-2, lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol), potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucroseEU and USA: $19.50

      African Union: $6.75

      Brazil: $10

      Colombia: $12
      mRNA-1273ModernaRNA-based100 μg

      11 or 15-dose vial

      0.5 mL per dose
      Intramuscularly

      2 doses 28 days apart
      Supplied as a frozen suspension stored between –50°C to –15°C

      Unopened vial: +2°C to +8°C for up to 30 days

      +8°C to +25°C for up to 24 hours

      After opening: +2°C to +25°C and discarded after 12 hours
      A synthetic messenger ribonucleic acid (mRNA) encoding the spike protein of SARS-CoV-2. The vaccine also contains the following ingredients: lipids (SM-102, 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (PEG2000-DMG), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)), tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate, and sucroseEU: $25.5

      USA: $15

      Argentina: $21.5

      Botswana: $28.8
      CVnCoVCureVacRNA-based12 μgIntramuscularly

      2 doses 28 days apart
      Concentrated CVnCoV will be stored frozen at –60°C (in clinical trial)

      CVnCoV must be diluted

      Unopened vial: 3 months at +2°C to +8°C

      Room temperature for 24 hours
      NANA
      AZD1222

      ChAdOx1 nCoV-19 vaccine
      AstraZeneca/University of OxfordNon-replicating viral vector5 × 1010 viral particles (standard dose)

      8 doses or 10 doses of 0.5 mL per vial
      Intramuscularly

      2 doses 4–12 weeks apart
      Do not freeze

      Unopened vial: 6 months (+2°C to +8°C)

      After opening: no more than 48 hours in a refrigerator (+2°C to +8°C)

      Used at temperature up to +30°C for a single period of up to 6 hours
      Chimpanzee Adenovirus encoding the SARS-CoV-2 spike glycoprotein (ChAdOx1-S)
      Prices were retrieved from https://www.unicef.org/supply/covid-19-vaccine-market-dashboard and https://www.theguardian.com/world/2021/aug/11/covid-19-vaccines-the-contracts-prices-and-profits.
      , not less than 2.5 × 108 infectious units (Inf.U)
      Prices were retrieved from https://www.unicef.org/supply/covid-19-vaccine-market-dashboard and https://www.theguardian.com/world/2021/aug/11/covid-19-vaccines-the-contracts-prices-and-profits.
      Produced in genetically modified human embryonic kidney (HEK) 293 cells and by recombinant DNA technology

      L-Histidine L-Histidine hydrochloride monohydrate Magnesium chloride hexahydrate Polysorbate 80 (E 433) Ethanol

      Sucrose Sodium chloride Disodium edetate (dihydrate)

      Water for injection
      $2.15 in the EU

      $4–6 elsewhere
      Ad26.COV2.SJohnson & JohnsonNon-replicating viral vector5 × 1010 viral particles

      10 doses of 0.5 mL per vial
      Intramuscularly

      A single dose
      Should be protected from light

      Supplied as a liquid suspension

      Unopened vial can be stored at +2°C to +8°C until the expiration date or at +9°C to +25°C for up to 12 hours

      After the first dose has been withdrawn, the vial is held between +2°C and +8°C for up to 6 hours or at room temperature for up to 2 hours
      Replication-incompetent recombinant adenovirus type 26 vector expressing the SARS-CoV-2 spike protein in a stabilized conformation. (5 × 1010 vp)

      Citric acid monohydrate, trisodium citrate dihydrate, ethanol, 2-hydroxypropyl-β-cyclodextrin (HBCD), polysorbate 80, sodium chloride, sodium hydroxide, and hydrochloric acid
      EU: $8.5

      USA: $10

      African Union: $10
      Gam-COVID-Vax

      Sputnik V
      Gamaleya Research InstituteNon-replicating viral vector1011 viral particles per dose for each recombinant adenovirus

      0.5 mL/dose
      Intramuscularly

      2 doses 21 days apart
      Transport: two forms: lyophilized or frozen

      Storage: +2°C to +8°C
      Two vector components, rAd26-S and rAd5-S

      Tris (hydroxymethyl) aminomethane, sodium chloride, sucrose, magnesium chloride hexahydrate, ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate, polysorbate-80, ethanol 95%, and water for injection
      <$10
      NVX-CoV2373NovavaxProtein-based5 μg protein and 50 μg Matrix-M adjuvantIntramuscularly

      2 doses 21 days apart
      Shipped in a ready-to-use liquid formulation

      Storage: +2°C to +8°C
      SARS-CoV-2 rS with matrix-M1 adjuvant (5 μg antigen and 50 μg adjuvant)$20.9 for Denmark

      COVAX: $3
      EpiVacCoronaVECTORProtein-based225 μg protein

      0.5 mL/dose
      Intramuscularly

      2 doses 21 days apart
      Storage between +2°C and +8°CNANA
      ZF2001Institute of Microbiology, Chinese Academy of Sciences, and Anhui Zhifei Longcom BiopharmaceuticalProtein-based25 μg protein

      0.5 mL/dose
      IntramuscularStorage between +2°C and +8°CNANA
      Convidecia™

      Ad5-nCoV
      CanSinoNon-replicating viral vector1010 viral particles per 0.5 mL in a vialIntramuscularly

      Single dose
      Supplied as a vial of 0.5 mL

      Storage between +2°C and +8°C

      Do not freeze
      The recombinant novel coronavirus vaccine (Adenovirus type 5 vector)

      Mannitol, sucrose, sodium chloride, magnesium chloride, polysorbate 80, glycerin, N-(2-hydroxyethyl), piperazine-N- (2-ethanesulfonic acid) (HEPES), sterile water for injection as solvent
      Pakistan private market: $27.2
      CoronaVacSinovac BiotechInactivated virus3 μg

      0.5 mL per dose
      Intramuscularly

      2 doses 28 days apart
      Supplied as a vial or syringe of 0.5 mL

      Do not freeze

      Protect from light

      Storage and transport between +2°C and +8°C

      Shake well before use

      Shelf-life: 12 months
      Inactivated CN02 strain of SARS-CoV-2 created with Vero cells

      Aluminium hydroxide, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate monohydrate, sodium chloride
      China: $29.75

      Ukraine: $18

      Philippines: $14.5

      Brazil: $10.3

      Cambodia: $10
      BBIBP-COrVSinopharm/Beijing Institute of Biological ProductsInactivated virus4 μg

      0.5 mL per dose
      Intramuscularly

      2 doses 21–28 days apart
      Supplied as pre-filled syringe or vial

      Cannot be frozen

      Protect from light

      Store and transport refrigerated (+2°C to +8°C)
      Inactivated virus

      19nCoV-CDC-Tan-HB02

      Excipients: disodium hydrogen phosphate, sodium chloride, sodium dihydrogen phosphate, aluminium hydroxide adjuvant
      Argentina, Mongolia: $15

      Senegal: $18.6

      China: $30

      Hungary: $36
      WuhanSinopharm/Chinese Academy of ScienceInactivated virusNANANANANA
      CovaxinBharat BiotechInactivated virus6 μg

      Single dose: 0.5 mL

      10-dose or 20-dose vial
      Intramuscularly

      2 doses 28 days apart
      Supplied as a single dose or multidose vial

      Do not freeze

      Stored at +2°C to +8°C
      6 μg whole-virion inactivated SARS-CoV-2 antigen (strain: NIV-2020-770), and other inactive ingredients such as aluminium hydroxide gel (250 μg), TLR 7/8 agonist (imidazoquinolinone) 15 μg, 2-phenoxyethanol 2.5 mg, and phosphate buffer saline® up to 0.5 mIndia: $3-5

      Brazil: $15

      Botswana: $16
      CIGB-66

      Abdala
      Center for Genetic Engineering and Biotechnology (CIGB)Protein-based0.05 mg recombinant protein

      0.5 mL per dose
      Intramuscularly

      3 doses at 0, 14, 28 days
      Supplied as a multidose vial

      Do not freeze

      Stored at +2°C to +8°C
      Recombinant protein of the SARS-CoV-2 virus receptor-binding domain (RBD) 0.05 mg

      Thiomersal 0.025 mg

      Aluminium hydroxide gel (Al³ +)

      Disodium hydrogen phosphate

      Sodium dihydrogen phosphate dihydrate

      Sodium chloride
      NA
      QazVac

      QazCovid-In
      Kazakh Research Institute for Biological Safety ProblemsInactivated virusIntramuscularly

      2 doses 21 days apart
      Stored at +2°C to +8°CNANA
      Coviran BarkatShifa Pharmed Industrial GroupInactivated virus5 μg inactivated purified virus

      0.5 mL per dose
      Intramuscularly

      2 doses 28 days apart
      Stored at +2°C to +8°CInactivated viral particles and a mixture

      2% adjuvant® Alhydrogel (aluminium hydroxide)
      NA
      KoviVacChumakov CenterInactivated virusNANANANANA
      Composition and conditions of use references are in the Supplementary Material Table S1.
      NA, not available information; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; EU, European Union.
      Table 2Phase III trials for coronavirus disease 2019 (COVID-19) vaccines
      VaccineAuthorStudy populationCut-off dateMain endpointSymptomatic COVID-19Severe COVID-19HospitalizationAny unsolicited serious adverse event
      VaccinePlaceboEfficacy (%, 95%CI)Cases among vaccine groupCases among placebo groupEfficacy (%, 95%CI)VaccinePlacebo
      BNT162b2 (RNA-based)Polack et al. [
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • Absalon J.
      • Gurtman A.
      • Lockhart S.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      ]
      USA, Argentina, Brazil, Germany, S. Africa, Turkey

      ≥16 years
      27th July 2020 to 14th November 2020

      Median follow-up: 2 months
      After dose 150/21 314275/21 25882% (75.6 to 86.9)0488.9% (20.1 to 99.7)NA0.6%0.5%
      After dose 2

      COVID-19 with onset at least 7 days after the second dose without prior infection
      8/18 198162/18 32595% (90.3 to 97.6)1475% (–152.6% to 99.5%)NA0.6%0.5%
      Thomas et al. [
      • Thomas S.J.
      • Moreira E.D.
      • Kitchin N.
      • Absalon J.
      • Gurtman A.
      • Lockhart S.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months.
      ]
      27th July 2020 to 13th March 2021

      6 months follow-up
      After dose 2

      COVID-19 with onset at least 7 days after the second dose without prior infection
      77/20 998850/20 71391.3% (89.0 to 93.2)12395.7% (73.9 to 99.9)NA1.2%0.7%
      Frenck et al. [
      • Frenck R.W.
      • Klein N.P.
      • Kitchin N.
      • Gurtman A.
      • Absalon J.
      • Lockhart S.
      • et al.
      Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents.
      ]
      USA

      12–15 years
      15th October 2020 to 12th January 2021

      2 months follow-up
      After dose 2

      COVID-19 with onset at least 7 days after the second dose without prior infection
      0/100516/978100% (75.3 to 100)00No cases of severe COVID-19 were observedNA0.4%0.1%
      mRNA-1273 (RNA-based)Baden et al. [
      • Baden L.R.
      • Sahly H.M.E.
      • Essink B.
      • Kotloff K.
      • Frey S.
      • Novak R.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      ]
      USA

      ≥18 years
      27th July 2020 to 21st November 2020

      Median follow-up of 64 days
      After dose 17/99639/107980.2% (55.2 to 92.5)NANANANANANA
      After dose

      COVID-19 with onset at least 14 days after the second dose without prior infection
      11/14 134185/14 07594.1% (89.3 to 96.8)030100% (no CI estimated)3 in the placebo group and 1 in the vaccine group0.6%0.6%
      El Sahly et al. [
      • El Sahly H.M.
      • Baden L.R.
      • Essink B.
      • Doblecki-Lewis S.
      • Martin J.M.
      • Anderson E.J.
      • et al.
      Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase.
      ]
      US

      ≥18 years
      26th March 202

      Median follow-up of 5.3 months post dose 2
      COVID-19 with onset at least 14 days after the second dose without prior infection55/14 287744/14 16493.2% (91 to 94.8)210698.2%NA0.7%0.6%
      CVnCoV (RNA-based)CureVac press communication [
      CureVac
      Press release. CureVac Final Data from Phase 2b/3 Trial of First-Generation COVID-19 Vaccine Candidate, CVnCoV, Demonstrates Protection in Age Group of 18 to 60 [Internet].
      ]
      Argentina, Belgium, Colombia, Dominican Republic, Germany, Mexico, Netherlands, Panama, Peru, SpainEstimated completion date: 15th May 2022COVID-19 of any severity40 000 adults

      83 cases among the vaccine group

      145 cases among the placebo group
      48%93677% against moderate and severe disease0 hospitalizations among the vaccine group

      6 hospitalizations among the placebo group
      OngoingOngoing
      AZD1222 (Non-replicating viral vector

      ChAdOx1 nCoV-19 vaccine
      Emary et al. [
      • Emary K.R.W.
      • Golubchik T.
      • Aley P.K.
      • Ariani C.V.
      • Angus B.
      • Bibi S.
      • et al.
      Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial.
      ]
      UK1st October 2020 to 14th January 202

      Median follow-up: not provided
      Symptomatic COVID-19 with onset at least 14 days after the second dose without prior infection59/4244210/4290Alpha: 70.4% (43.6 to 84.5)

      Non-VOC lineages: 81.5% (67.9 to 89.4)
      NANANAThere were no cases of hospitalization or deathNANA
      Voysey et al. [
      • Voysey M.
      • Clemens S.A.C.
      • Madhi S.A.
      • Weckx L.Y.
      • Folegatti P.M.
      • Aley P.K.
      • et al.
      Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.
      ]
      UK/Brazil/South Africa

      ≥18 years
      23rd April 2020 to 7th December 2020

      Median follow-up post dose 2: 53–90 days according to the dose gap
      Symptomatic COVID-19 with onset at least 14 days after the second dose without prior infection84/8597248/858166.7% (57.4% to 74%)015Efficacy against hospitalization from 22 days after vaccination: 100%2 hospitalizations among the vaccine group

      22 hospitalizations among the placebo group
      0.7%0.8%
      Madhi et al. [
      • Madhi S.A.
      • Baillie V.
      • Cutland C.L.
      • Voysey M.
      • Koen A.L.
      • Fairlie L.
      • et al.
      Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant.
      ]
      South Africa

      ≥18 years
      24th June 2020 to 9th November 2020

      Median follow-up post dose 2: 156–121 days (vaccinated – placebo)
      Mild to moderate COVID-19 with onset at least 14 days after the second dose without prior infection19/75023/71721.9 (–49.9 to 59.8)00No participant had severe COVID-19Zero hospitalizations14 events13 events
      Against Beta variant at least 14 days after the second dose without prior infection19/75020/71410.4% (–76.4 to 54.8)00
      Press communication [
      • AstraZeneca
      AZD1222 US Phase III trial met primary efficacy endpoint in preventing COVID-19 at interim analysis [Internet].
      ]
      USA

      ≥18 years
      25th March 2021Preventing symptomatic COVID-19141 symptomatic cases among 32 449 participants76% (68 to 82)NANA100%Zero hospitalizations among the vaccine group

      Not specified for the placebo group
      NANA
      Ad26.COV2.S (Non-replicating viral vector)US FDA and EMA [
      US FDA
      Janssen Ad26.COV2.S (COVID-19. Vaccine VRBPAC briefing document.
      ,]
      Brazil, Chile, Argentina, Colombia, Peru, Mexico, US, South Africa

      ≥18 years

      Variant D614G 96.4% in the US

      Beta (94.5% in South Africa)

      Variant P2 (69.4% in Brazil)
      22nd January 2021

      Median follow-up of 2 months
      Prevent confirmed, moderate to severe/critical COVID-19 at least 14 days after vaccination without prior infection116/19 514348/19 544All: 66.9% (59.1 to 73.4)

      USA: 74.4% (65 to 81.6)

      South Africa: 52% (30.3 to 67.4)

      Latin America: 64.7% (54.1 to 73)
      1460All: 76.7% (54.6 to 89.1)2 hospitalizations among the vaccine group

      29 hospitalizations among the placebo group
      0.4%0.4%
      Prevent confirmed, moderate to severe/critical COVID-19 at least 28 days after vaccination without prior infection66/19 306193/19 178All: 66.1% (55.0 to 74.8)

      USA: 72% (58.2 to 81.7)

      South Africa: 64% (41.2 to 78.7)

      Latin America: 61% (46.9 to 71.8)
      534All: 85.4% (54.2 to 96.9)0 hospitalizations among the vaccine group

      16 hospitalizations among the placebo group
      Gam-COVID-Vax

      Sputnik V (Non-replicating viral vector)
      Logunov et al. [
      • Logunov D.Y.
      • Dolzhikova I.V.
      • Shcheblyakov D.V.
      • Tukhvatulin A.I.
      • Zubkova O.V.
      • Dzharullaeva A.S.
      • et al.
      Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia.
      ]
      Russia

      ≥18 years
      7th September 2020 to 24th November 2020

      Median follow-up post dose 1: 48 days
      First confirmed COVID-19 after the first dose79/16 42796/543573.1% (63.7 to 80.1)NANA0.3%0.4%
      First confirmed COVID-19 after the second dose16/14 96462/490291.6% (85.6 to 95.2)020100% (94.4 to 100)

      Moderate or severe
      NA
      NVX-CoV2373 (Protein-based)Shinde et al. [
      • Shinde V.
      • Bhikha S.
      • Hoosain Z.
      • Archary M.
      • Bhorat Q.
      • Fairlie L.
      • et al.
      Efficacy of NVX-CoV2373 Covid-19 vaccine against the B.1.351 variant.
      ]
      South Africa

      ≥18 years

      Beta: 90% of cases in South Africa
      17th August 2020 to 25th November, 2020

      Median follow-up post dose 2: 45 days
      Preventing symptomatic COVID-19 at least 7 days after the 2nd dose without prior infection44/135729/1327All: 49.4% (6.1 to 72.8%)

      HIV-negative participants: 60% (19.9 to 80.1)
      NANANANA0.4%0.2%
      Heath et al. [
      • Heath P.T.
      • Galiza E.P.
      • Baxter D.N.
      • Boffito M.
      • Browne D.
      • Burns F.
      • et al.
      Safety and efficacy of NVX-CoV2373 Covid-19 vaccine.
      ]
      UK

      ≥18 years
      Median follow-up post dose 2: 3 monthsSymptomatic COVID-19 at least 7 days after the 2nd dose without prior infection10 cases96 cases89.7% (80.2 to 94.6)

      86.3% (71.3 to 93.5) against Alpha
      011 severe COVID-19 in placebo group0.5%0.5%
      Novavax press release [
      Novavax
      Novavax COVID-19 vaccine demonstrates 89.3% efficacy in UK phase 3 trial | Novavax Inc. - IR Site [Internet].
      ]
      USA and Mexico25th January 2021 to 30th April 2021 (Alpha predominant)

      Follow-up: not available
      Symptomatic COVID-19 with onset at least 7 days after the second dose without prior infection146390.4% (82.9 to 94.6)

      93.2% (83.9 to 97.1) against variants (mainly Alpha)
      NANANANANANA
      Convidecia™

      Ad5-nCoV (Non-replicating viral vector)
      CanSino Biologics Inc document [
      CanSino Biologics Inc
      Inside information NMPA’s acceptence of application for conditional marketing authorization of recombinant novel coronavirus vaccine (Adenovirus Type 5 Vector).
      ]
      Pakistan, Mexico, Russia, Chile and Argentina

      ≥18 years
      8th February 2021

      Follow-up: not available
      Symptomatic COVID-19 disease 14 days after single doseNANA68.83%NANA95.47%NANANA
      Symptomatic COVID-19 disease 28 days after single doseNANA65.28%NANA90.07%NANANA
      CoronaVac (Inactivated virus)Sinovac document [
      Sinovac Biotech Ltd
      Sinovac announces phase III results of Its COVID-19 vaccine-SINOVAC - supply vaccines to eliminate human diseases [Internet].
      ]
      Brazil, Turkey, Indonesia

      ≥18 years
      16th December 2020

      Follow-up: not available
      Symptomatic COVID-19 at least 14 days after two dosesBrazil: 253 cases/12 396 health workers

      Turkey: 29 cases/1322
      Brazil all: 50,65%

      Turkey: 83.5%

      Indonesia: 65%
      NANABrazil: 100%NANANA
      Tanriover et al. [
      • Tanriover M.D.
      • Doğanay H.L.
      • Akova M.
      • Güner H.R.
      • Azap A.
      • Akhan S.
      • et al.
      Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey.
      ]
      Turkey

      ≥18 years
      15th September 2020 to 6th January 2021

      Median follow-up (after randomization): 43 days
      Symptomatic COVID-19 at least 14 days after two doses9/655932/347083.5% (65.4 to 92.1)NANANA1 hospitalization in the placebo group

      0 hospitalizations in the vaccine group
      0.1%0.1%
      BBIBP-CorV (inactivated virus)Al Kaabi et al. [
      • Al Kaabi N.
      • Zhang Y.
      • Xia S.
      • Yang Y.
      • Al Qahtani M.M.
      • Abdulrazzaq N.
      • et al.
      Effect of 2 inactivated SARS-CoV-2 vaccines on symptomatic COVID-19 infection in adults: a randomized clinical trial.
      ]
      Bahrain, China, Pakistan, and the UAE

      ≥18 years
      16th July 2020 to 20th December 2020

      Median follow-up (14 days after the 2nd dose): 77 days
      Symptomatic COVID-19, 14 days after the second dose without prior infection at baseline21/12 72695/12 73778.1 (64.8 to 86.3)02100% (NA)NA0.4%0.6%
      Wuhan inactivated vaccineAl Kaabi et al. [
      • Al Kaabi N.
      • Zhang Y.
      • Xia S.
      • Yang Y.
      • Al Qahtani M.M.
      • Abdulrazzaq N.
      • et al.
      Effect of 2 inactivated SARS-CoV-2 vaccines on symptomatic COVID-19 infection in adults: a randomized clinical trial.
      ]
      Bahrain, China, Pakistan, and the UAE

      ≥18 years
      16th July 2020 to 20th December 2020

      Median follow-up (14 days after the 2nd dose): 77 days
      Symptomatic COVID-19, 14 days after the second dose without prior infection at baseline26/12 74395/12 73772.8% (58.1 to 82.4)02100% (NA)NA0.5%0.6%
      COVAXIN (inactivated virus)Bharat Biotech [
      Bharat Biotech
      Bharat biotech announces phase 3 results of COVAXIN®: India’s first COVID-19 vaccine demonstrates interim clinical efficacy of 81% [Internet].
      ]
      India

      ≥18 years
      Median follow-up: not availableSymptomatic COVID-19, 14 days after the second dose without prior infection at baseline127 symptomatic cases among 25 800 participants78% (61 to 88)NANA100% (60 to 100)NANANA
      Abdala (Protein-based)Press release [
      El Centro de Ingeniería Genética y Biotecnología. Vacuna Abdala
      100% de eficacia ante la enfermedad severa y la muerte en su ensayo fase III [Internet].
      ]
      CubaMedian follow-up: not availableCOVID-19 (not specified)NANA92.3%NANANANA
      At the time of the review, we did not find any phase III trial results published or available for QazVax (inactivated virus), KoviVac, COVIran Barekat, EpiVacCorona, ZF2001 and Sputnik V Light.
      NA, no information available.
      Fig. 1
      Fig. 1Vaccine efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from clinical trials (in % and 95%CI) according to the number of doses. Confidence intervals are delimited by the grey rectangular area.
      Table 3Coronavirus disease 2019 (COVID-19) vaccines and variants
      SARS-CoV-2 variantsB.1.1.7

      501Y.V1
      B.1.551

      501Y.V2
      B.1.1.28.1.P1

      501Y.V3
      B.1.617.2 (and AY sublineages)B.1.617.1
      WHO nomenclatureAlphaBetaGammaDeltaKappa
      Key spike mutations69/70del, 144del, N501Y, A570D, D614G, P681H, T716I, S982A, D1118HD80A, D215G, 241/243del, K417N, E484K, N501Y, D614G, A701VL18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G H655Y, T1027I, V1176FT19R, T95I, G142D, E156-, F157-, R158G, L452R, T478K, D614G, P681R, D950N ± (V70F, A222V, W258L, K417N)G142D, E154K, L452R, E484Q, D614G, P681R, Q1071H ± (T95I)
      First detectionUK

      September 2020
      South Africa

      September 2020
      Brazil and Japan

      December 2020
      India

      December 2020
      India

      December 2020
      Transmission compared to non-VOC/VOI+56% in the UK [
      • Volz E.
      • Mishra S.
      • Chand M.
      • Barrett J.C.
      • Johnson R.
      • Geidelberg L.
      • et al.
      Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England.
      ]

      +56–74% in Denmark, Switzerland, US [
      • Davies N.G.
      • Abbott S.
      • Barnard R.C.
      • Jarvis C.I.
      • Kucharski A.J.
      • Munday J.D.
      • et al.
      Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England.
      ]

      43-100% higher reproductive number [
      • Campbell F.
      • Archer B.
      • Laurenson-Schafer H.
      • Jinnai Y.
      • Konings F.
      • Batra N.
      • et al.
      Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021.
      ]
      +50% in South Africa [
      • Pearson C.A.B.
      • Russell T.W.
      • Davies N.
      • Kucharski A.J.
      • Edmunds W.J.
      • Eggo R.M.
      CMMID COVID-19 working group
      Estimates of severity and transmissibility of novel SARS-CoV-2 variant 501Y.V2 in South Africa [Internet].
      ]
      +160% in Brazil [
      • Coutinho R.M.
      • Marquitti F.M.D.
      • Ferreira L.S.
      • Borges M.E.
      • Silva RLP da
      • Canton O.
      • et al.
      Model-based estimation of transmissibility and reinfection of SARS-CoV-2 P.1 variant.
      ,
      • Faria N.R.
      • Mellan T.A.
      • Whittaker C.
      • Claro I.M.
      • Candido D. da S.
      • Mishra S.
      • et al.
      Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil.
      ]
      +40 to 60% in the UK (compared to Alpha)

      +97% higher reproductive number [
      • Campbell F.
      • Archer B.
      • Laurenson-Schafer H.
      • Jinnai Y.
      • Konings F.
      • Batra N.
      • et al.
      Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021.
      ]
      NA
      Risk of mortalityIncreased 61–64%mortality in the UK [
      • Davies N.G.
      • Jarvis C.I.
      • Edmunds W.J.
      • Jewell N.P.
      • Diaz-Ordaz K.
      • Keogh R.H.
      Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7.
      ]
      NANAMay cause more severe cases than Alpha [
      • Twohig K.A.
      • Nyberg T.
      • Zaidi A.
      • Thelwall S.
      • Sinnathamby M.A.
      • Aliabadi S.
      • et al.
      Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study.
      ]
      NA
      Impact on post-vaccination sera (reduction in neutralization activity compared to the original SARS-CoV-2 or D614G)No/minimal

      0–3.3-fold reduction for BNT162b2 [
      • Wang P.
      • Nair M.S.
      • Liu L.
      • Iketani S.
      • Luo Y.
      • Guo Y.
      • et al.
      Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.
      ,
      • Liu Y.
      • Liu J.
      • Xia H.
      • Zhang X.
      • Fontes-Garfias C.R.
      • Swanson K.A.
      • et al.
      Neutralizing activity of BNT162b2-elicited serum.
      ,
      • Xie X.
      • Liu Y.
      • Liu J.
      • Zhang X.
      • Zou J.
      • Fontes-Garfias C.R.
      • et al.
      Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera.
      ,
      • Hoffmann M.
      • Arora P.
      • Groß R.
      • Seidel A.
      • Hörnich B.F.
      • Hahn A.S.
      • et al.
      SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies.
      ,
      • Collier D.A.
      • De Marco A.
      • Ferreira I.A.T.M.
      • Meng B.
      • Datir R.
      • Walls A.C.
      • et al.
      Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.
      ,
      • Skelly D.T.
      • Harding A.C.
      • Gilbert-Jaramillo J.
      • Knight M.
      • Longet S.
      • Anthony B.
      • et al.
      Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection.
      ,
      • Garcia-Beltran W.F.
      • Lam E.C.
      • St Denis K.
      • Nitido A.D.
      • Garcia Z.H.
      • Hauser B.M.
      • et al.
      Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.
      ,
      • Bates T.A.
      • Leier H.C.
      • Lyski Z.L.
      • McBride S.K.
      • Coulter F.J.
      • Weinstein J.B.
      • et al.
      Neutralization of SARS-CoV-2 variants by convalescent and vaccinated serum.
      ,
      • Supasa P.
      • Zhou D.
      • Dejnirattisai W.
      • Liu C.
      • Mentzer A.J.
      • Ginn H.M.
      • et al.
      Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera.
      ,
      • Ikegame S.
      • Siddiquey M.N.A.
      • Hung C.-T.
      • Haas G.
      • Brambilla L.
      • Oguntuyo K.Y.
      • et al.
      Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants.
      ,
      • Wang Z.
      • Schmidt F.
      • Weisblum Y.
      • Muecksch F.
      • Barnes C.O.
      • Finkin S.
      • et al.
      mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.
      ,
      • Dejnirattisai W.
      • Zhou D.
      • Supasa P.
      • Liu C.
      • Mentzer A.J.
      • Ginn H.M.
      • et al.
      Antibody evasion by the P.1 strain of SARS-CoV-2.
      ,
      • Lustig Y.
      • Nemet I.
      • Kliker L.
      • Zuckerman N.
      • Yishai R.
      • Alroy-Preis S.
      • et al.
      Neutralizing response against variants after SARS-CoV-2 infection and one dose of BNT162b2.
      ,
      • Uriu K.
      • Kimura I.
      • Shirakawa K.
      • Takaori-Kondo A.
      • Nakada T.
      • Kaneda A.
      • et al.
      Ineffective neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine sera.
      ], mRNA-1273 [
      • Edara V.V.
      • Hudson W.H.
      • Xie X.
      • Ahmed R.
      • Suthar M.S.
      Neutralizing antibodies against SARS-CoV-2 variants after infection and vaccination.
      ,
      • Wang P.
      • Nair M.S.
      • Liu L.
      • Iketani S.
      • Luo Y.
      • Guo Y.
      • et al.
      Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.
      ,
      • Garcia-Beltran W.F.
      • Lam E.C.
      • St Denis K.
      • Nitido A.D.
      • Garcia Z.H.
      • Hauser B.M.
      • et al.
      Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.
      ,
      • Wu K.
      • Werner A.P.
      • Moliva J.I.
      • Koch M.
      • Choi A.
      • Stewart-Jones G.B.E.
      • et al.
      mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants.
      ]

      No reduction for Sputnik V, Covaxin, BBIBP-CorV [
      • Ikegame S.
      • Siddiquey M.N.A.
      • Hung C.-T.
      • Haas G.
      • Brambilla L.
      • Oguntuyo K.Y.
      • et al.
      Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants.
      ,
      • Wang G.-L.
      • Wang Z.-Y.
      • Duan L.-J.
      • Meng Q.-C.
      • Jiang M.-D.
      • Cao J.
      • et al.
      Susceptibility of circulating SARS-CoV-2 variants to neutralization.
      ,
      • Sapkal G.N.
      • Yadav P.D.
      • Ella R.
      • Deshpande G.R.
      • Sahay R.R.
      • Gupta N.
      • et al.
      Neutralization of UK-variant VUI-202012/01 with COVAXIN vaccinated human serum.
      ]

      1.5–4.1-fold reduction for CoronaVac [
      • Wang G.-L.
      • Wang Z.-Y.
      • Duan L.-J.
      • Meng Q.-C.
      • Jiang M.-D.
      • Cao J.
      • et al.
      Susceptibility of circulating SARS-CoV-2 variants to neutralization.
      ,
      • Chen Y.
      • Shen H.
      • Huang R.
      • Tong X.
      • Wu C.
      Serum neutralising activity against SARS-CoV-2 variants elicited by CoronaVac.
      ,
      • Acevedo M.L.
      • Alonso-Palomares L.
      • Bustamante A.
      • Gaggero A.
      • Paredes F.
      • Cortés C.P.
      • et al.
      Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda.
      ]

      2.1-fold reduction for AZD1222 [
      • Supasa P.
      • Zhou D.
      • Dejnirattisai W.
      • Liu C.
      • Mentzer A.J.
      • Ginn H.M.
      • et al.
      Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera.
      ] and NVX- CoV2373 [
      • Shen X.
      • Tang H.
      • McDanal C.
      • Wagh K.
      • Fischer W.
      • Theiler J.
      • et al.
      SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines.
      ]
      Minimal to substantial

      No reduction for BBIBP-CorV [
      • Wang G.-L.
      • Wang Z.-Y.
      • Duan L.-J.
      • Meng Q.-C.
      • Jiang M.-D.
      • Cao J.
      • et al.
      Susceptibility of circulating SARS-CoV-2 variants to neutralization.
      ,
      • Huang B.
      • Dai L.
      • Wang H.
      • Hu Z.
      • Yang X.
      • Tan W.
      • et al.
      Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines.
      ]

      1.3–38.45-fold reduction for BNT162b2 [
      • Planas D.
      • Bruel T.
      • Grzelak L.
      • Guivel-Benhassine F.
      • Staropoli I.
      • Porrot F.
      • et al.
      Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies.
      ,
      • Wang P.
      • Nair M.S.
      • Liu L.
      • Iketani S.
      • Luo Y.
      • Guo Y.
      • et al.
      Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.
      ,
      • Liu Y.
      • Liu J.
      • Xia H.
      • Zhang X.
      • Fontes-Garfias C.R.
      • Swanson K.A.
      • et al.
      Neutralizing activity of BNT162b2-elicited serum.
      ,
      • Xie X.
      • Liu Y.
      • Liu J.
      • Zhang X.
      • Zou J.
      • Fontes-Garfias C.R.
      • et al.
      Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera.
      ,
      • Hoffmann M.
      • Arora P.
      • Groß R.
      • Seidel A.
      • Hörnich B.F.
      • Hahn A.S.
      • et al.
      SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies.
      ,
      • Collier D.A.
      • De Marco A.
      • Ferreira I.A.T.M.
      • Meng B.
      • Datir R.
      • Walls A.C.
      • et al.
      Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.
      ,
      • Garcia-Beltran W.F.
      • Lam E.C.
      • St Denis K.
      • Nitido A.D.
      • Garcia Z.H.
      • Hauser B.M.
      • et al.
      Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.
      ,
      • Bates T.A.
      • Leier H.C.
      • Lyski Z.L.
      • McBride S.K.
      • Coulter F.J.
      • Weinstein J.B.
      • et al.
      Neutralization of SARS-CoV-2 variants by convalescent and vaccinated serum.
      ,
      • Wang Z.
      • Schmidt F.
      • Weisblum Y.
      • Muecksch F.
      • Barnes C.O.
      • Finkin S.
      • et al.
      mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.
      ,
      • Dejnirattisai W.
      • Zhou D.
      • Supasa P.
      • Liu C.
      • Mentzer A.J.
      • Ginn H.M.
      • et al.
      Antibody evasion by the P.1 strain of SARS-CoV-2.
      ,
      • Tada T.
      • Dcosta B.M.
      • Samanovic-Golden M.
      • Herati R.S.
      • Cornelius A.
      • Mulligan M.J.
      • et al.
      Neutralization of viruses with European, South African, and United States SARS-CoV-2 variant spike proteins by convalescent sera and BNT162b2 mRNA vaccine-elicited antibodies.
      ]

      3.3–23.45-fold reduction for mRNA-1273 [
      • Wang P.
      • Nair M.S.
      • Liu L.
      • Iketani S.
      • Luo Y.
      • Guo Y.
      • et al.
      Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.
      ,
      • Garcia-Beltran W.F.
      • Lam E.C.
      • St Denis K.
      • Nitido A.D.
      • Garcia Z.H.
      • Hauser B.M.
      • et al.
      Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.
      ,
      • Wu K.
      • Werner A.P.
      • Moliva J.I.
      • Koch M.
      • Choi A.
      • Stewart-Jones G.B.E.
      • et al.
      mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants.
      ,
      • Edara V.V.
      • Norwood C.
      • Floyd K.
      • Lai L.
      • Davis-Gardner M.E.
      • Hudson W.H.
      • et al.
      Infection- and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant.
      ,
      • Shen X.
      • Tang H.
      • Pajon R.
      • Smith G.
      • Glenn G.M.
      • Shi W.
      • et al.
      Neutralization of SARS-CoV-2 variants B.1.429 and B.1.351.
      ], AZD1222 [
      • Davis C.
      • Logan N.
      • Tyson G.
      • Orton R.
      • Harvey W.
      • Haughney J.
      • et al.
      Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination.
      ]

      3.3–5.3-fold reduction CoronaVac [
      • Wang G.-L.
      • Wang Z.-Y.
      • Duan L.-J.
      • Meng Q.-C.
      • Jiang M.-D.
      • Cao J.
      • et al.
      Susceptibility of circulating SARS-CoV-2 variants to neutralization.
      ,
      • Chen Y.
      • Shen H.
      • Huang R.
      • Tong X.
      • Wu C.
      Serum neutralising activity against SARS-CoV-2 variants elicited by CoronaVac.
      ]

      6.1-fold reduction for Sputnik V [
      • Ikegame S.
      • Siddiquey M.N.A.
      • Hung C.-T.
      • Haas G.
      • Brambilla L.
      • Oguntuyo K.Y.
      • et al.
      Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants.
      ]

      14.5-fold reduction for NVX-CoV2373 [
      • Shen X.
      • Tang H.
      • Pajon R.
      • Smith G.
      • Glenn G.M.
      • Shi W.
      • et al.
      Neutralization of SARS-CoV-2 variants B.1.429 and B.1.351.
      ]
      Minimal to moderate

      1.2–7.6-fold reduction for BNT162b2

      3.2–4.5-fold reduction for mRNA-1273 [
      • Liu Y.
      • Liu J.
      • Xia H.
      • Zhang X.
      • Fontes-Garfias C.R.
      • Swanson K.A.
      • et al.
      Neutralizing activity of BNT162b2-elicited serum.
      ,
      • Hoffmann M.
      • Arora P.
      • Groß R.
      • Seidel A.
      • Hörnich B.F.
      • Hahn A.S.
      • et al.
      SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies.
      ,
      • Garcia-Beltran W.F.
      • Lam E.C.
      • St Denis K.
      • Nitido A.D.
      • Garcia Z.H.
      • Hauser B.M.
      • et al.
      Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.
      ]

      9-fold reduction for AZD1222 [
      • Dejnirattisai W.
      • Zhou D.
      • Supasa P.
      • Liu C.
      • Mentzer A.J.
      • Ginn H.M.
      • et al.
      Antibody evasion by the P.1 strain of SARS-CoV-2.
      ]

      7.5-fold reduction for CoronaVac [
      • Chen Y.
      • Shen H.
      • Huang R.
      • Tong X.
      • Wu C.
      Serum neutralising activity against SARS-CoV-2 variants elicited by CoronaVac.
      ,
      • Acevedo M.L.
      • Alonso-Palomares L.
      • Bustamante A.
      • Gaggero A.
      • Paredes F.
      • Cortés C.P.
      • et al.
      Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda.
      ]

      3.4-fold reduction for Ad26.COV2.S [
      • Jongeneelen M.
      • Kaszas K.
      • Veldman D.
      • Huizingh J.
      • Vlugt R van der
      • Schouten T.
      • et al.
      Ad26.COV2.S elicited neutralizing activity against Delta and other SARS-CoV-2 variants of concern.
      ]

      2.8-fold reduction for Sputnik V [
      • Lopez Ledesma M.M.G.
      • Sanchez L.
      • Ojeda D.S.
      • Rouco S.O.
      • Rossi A.H.
      • Varese A.
      • et al.
      Temporal increase in neutralization potency of SARS-CoV-2 antibodies and reduced viral variant escape after Sputnik V vaccination.
      ]
      3–3.9-fold reduction for mRNA-1273 [
      • Edara V.-V.
      • Pinsky B.A.
      • Suthar M.S.
      • Lai L.
      • Davis-Gardner M.E.
      • Floyd K.
      • et al.
      Infection and vaccine-induced neutralizing-antibody responses to the SARS-CoV-2 B.1.617 variants.
      ,
      • Tada T.
      • Zhou H.
      • Samanovic M.I.
      • Dcosta B.M.
      • Cornelius A.
      • Mulligan M.J.
      • et al.
      Comparison of neutralizing antibody titers elicited by mrna and adenoviral vector vaccine against SARS-CoV-2 variants.
      ,
      • Choi A.
      • Koch M.
      • Wu K.
      • Dixon G.
      • Oestreicher J.
      • Legault H.
      • et al.
      Serum neutralizing activity of mRNA-1273 against SARS-CoV-2 variants.
      ]

      1.4–11.1-fold reduction for BN162b2 [
      • Davis C.
      • Logan N.
      • Tyson G.
      • Orton R.
      • Harvey W.
      • Haughney J.
      • et al.
      Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination.
      ,
      • Edara V.-V.
      • Pinsky B.A.
      • Suthar M.S.
      • Lai L.
      • Davis-Gardner M.E.
      • Floyd K.
      • et al.
      Infection and vaccine-induced neutralizing-antibody responses to the SARS-CoV-2 B.1.617 variants.
      ,
      • Tada T.
      • Zhou H.
      • Samanovic M.I.
      • Dcosta B.M.
      • Cornelius A.
      • Mulligan M.J.
      • et al.
      Comparison of neutralizing antibody titers elicited by mrna and adenoviral vector vaccine against SARS-CoV-2 variants.
      ,
      • Liu J.
      • Liu Y.
      • Xia H.
      • Zou J.
      • Weaver S.C.
      • Swanson K.A.
      • et al.
      BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants.
      ,
      • Liu C.
      • Ginn H.M.
      • Dejnirattisai W.
      • Supasa P.
      • Wang B.
      • Tuekprakhon A.
      • et al.
      Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum.
      ,
      • Lustig Y.
      • Zuckerman N.
      • Nemet I.
      • Atari N.
      • Kliker L.
      • Regev-Yochay G.
      • et al.
      Neutralising capacity against Delta (B.1.617.2) and other variants of concern following Comirnaty (BNT162b2, BioNTech/Pfizer) vaccination in health care workers.
      ]

      3.1–9 for AZD1222 [
      • Davis C.
      • Logan N.
      • Tyson G.
      • Orton R.
      • Harvey W.
      • Haughney J.
      • et al.
      Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination.
      ,
      • Liu C.
      • Ginn H.M.
      • Dejnirattisai W.
      • Supasa P.
      • Wang B.
      • Tuekprakhon A.
      • et al.
      Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum.
      ,
      • Mlcochova P.
      • Kemp S.
      • Dhar M.S.
      • Papa G.
      • Meng B.
      • Ferreira I.A.T.M.
      • et al.
      SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion.
      ]

      1.6–5.4-fold reduction for Ad26.COV2.S [
      • Jongeneelen M.
      • Kaszas K.
      • Veldman D.
      • Huizingh J.
      • Vlugt R van der
      • Schouten T.
      • et al.
      Ad26.COV2.S elicited neutralizing activity against Delta and other SARS-CoV-2 variants of concern.
      ,
      • Tada T.
      • Zhou H.
      • Samanovic M.I.
      • Dcosta B.M.
      • Cornelius A.
      • Mulligan M.J.
      • et al.
      Comparison of neutralizing antibody titers elicited by mrna and adenoviral vector vaccine against SARS-CoV-2 variants.
      ]

      2.5-fold for CoronaVac [
      • Hu J.
      • Wei X.
      • Xiang J.
      • Peng P.
      • Xu F.
      • Wu K.
      • et al.
      Reduced neutralization of SARS-CoV-2 B.1.617 variant by inactivated and RBD-subunit vaccine.
      ]

      3-fold for ZF2001 [
      • Hu J.
      • Wei X.
      • Xiang J.
      • Peng P.
      • Xu F.
      • Wu K.
      • et al.
      Reduced neutralization of SARS-CoV-2 B.1.617 variant by inactivated and RBD-subunit vaccine.
      ]

      2.5-fold for Sputnik V [
      • Gushchin V.A.
      • Dolzhikova I.V.
      • Shchetinin A.M.
      • Odintsova A.S.
      • Siniavin A.E.
      • Nikiforova M.A.
      • et al.
      Neutralizing activity of sera from Sputnik V-vaccinated people against variants of concern (VOC: B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.3) and Moscow endemic SARS-CoV-2 variants.
      ]

      4.6-fold for Covaxin [
      • Yadav P.D.
      • Sapkal G.N.
      • Abraham P.
      • Ella R.
      • Deshpande G.
      • Patil D.Y.
      • et al.
      Neutralization of variant under investigation B.1.617.1 with sera of BBV152 vaccinees.
      ].
      2.6–7.5-fold reduction for BNT162b2 [
      • Davis C.
      • Logan N.
      • Tyson G.
      • Orton R.
      • Harvey W.
      • Haughney J.
      • et al.
      Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination.
      ,
      • Edara V.-V.
      • Pinsky B.A.
      • Suthar M.S.
      • Lai L.
      • Davis-Gardner M.E.
      • Floyd K.
      • et al.
      Infection and vaccine-induced neutralizing-antibody responses to the SARS-CoV-2 B.1.617 variants.
      ,
      • Liu J.
      • Liu Y.
      • Xia H.
      • Zou J.
      • Weaver S.C.
      • Swanson K.A.
      • et al.
      BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants.
      ,
      • Hoffmann M.
      • Hofmann-Winkler H.
      • Krüger N.
      • Kempf A.
      • Nehlmeier I.
      • Graichen L.
      • et al.
      SARS-CoV-2 variant B.1.617 is resistant to Bamlanivimab and evades antibodies induced by infection and vaccination.
      ]

      3.4–7-fold reduction for mRNA-1273 [
      • Choi A.
      • Koch M.
      • Wu K.
      • Dixon G.
      • Oestreicher J.
      • Legault H.
      • et al.
      Serum neutralizing activity of mRNA-1273 against SARS-CoV-2 variants.
      ]

      1–2.6-fold reduction for AZD1222 [
      • Davis C.
      • Logan N.
      • Tyson G.
      • Orton R.
      • Harvey W.
      • Haughney J.
      • et al.
      Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination.
      ,
      • Liu J.
      • Liu Y.
      • Xia H.
      • Zou J.
      • Weaver S.C.
      • Swanson K.A.
      • et al.
      BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants.
      ,
      • Yadav P.D.
      • Sapkal G.N.
      • Abraham P.
      • Ella R.
      • Deshpande G.
      • Patil D.Y.
      • et al.
      Neutralization of variant under investigation B.1.617.1 with sera of BBV152 vaccinees.
      ]
      Effectiveness against SARS-CoV-2 infection (fully vaccinated)BNT162b2:

      78–95% [
      • Abu-Raddad L.J.
      • Chemaitelly H.
      • Butt A.A.
      Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants.
      ,
      • Dagan N.
      • Barda N.
      • Kepten E.
      • Miron O.
      • Perchik S.
      • Katz M.A.
      • et al.
      BNT162b2 mRNA Covid-19 vaccine in a Nationwide mass vaccination setting.
      ,
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • Anis E.
      • Singer S.R.
      • Khan F.
      • et al.
      Nationwide vaccination campaign with BNT162b2 in Israel demonstrates high vaccine effectiveness and marked declines in incidence of SARS-CoV-2 infections and COVID-19 cases, hospitalizations, and deaths [Internet].
      ,
      • Pouwels K.B.
      • Pritchard E.
      • Matthews P.C.
      • Stoesser N.
      • Eyre D.W.
      • Vihta K.-D.
      • et al.
      Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.
      ] mRNA-1273: 84–99% [
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Al Khatib H.A.
      • Tang P.
      • Hasan M.R.
      • et al.
      mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar.
      ,
      • Seppälä E.
      • Veneti L.
      • Starrfelt J.
      • Danielsen A.S.
      • Bragstad K.
      • Hungnes O.
      • et al.
      Vaccine effectiveness against infection with the delta (B.1.617.2) variant, Norway, April to August 2021.
      ]

      AZD1222: 79% [
      • Pouwels K.B.
      • Pritchard E.
      • Matthews P.C.
      • Stoesser N.
      • Eyre D.W.
      • Vihta K.-D.
      • et al.
      Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.
      ]
      BNT162b2: 75% [
      • Abu-Raddad L.J.
      • Chemaitelly H.
      • Butt A.A.
      Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants.
      ] mRNA-1273: 96% [
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Al Khatib H.A.
      • Tang P.
      • Hasan M.R.
      • et al.
      mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar.
      ]
      NABNT162b2: 42–79% [
      • Sheikh A.
      • McMenamin J.
      • Taylor B.
      • Robertson C.
      SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness.
      ,
      • Pouwels K.B.
      • Pritchard E.
      • Matthews P.C.
      • Stoesser N.
      • Eyre D.W.
      • Vihta K.-D.
      • et al.
      Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.
      ,
      • Tang P.
      • Hasan M.R.
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Khatib H.A.A.
      • et al.
      BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the Delta (B.1.617.2) variant in Qatar.
      ,
      • Puranik A.
      • Lenehan P.J.
      • Silvert E.
      • Niesen M.J.M.
      • Corchado-Garcia J.
      • O’Horo J.C.
      • et al.
      Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence.
      ,
      • Goldberg Y.
      • Mandel M.
      • Bar-On Y.M.
      • Bodenheimer O.
      • Freedman L.
      • Haas E.J.
      • et al.
      Waning immunity of the BNT162b2 vaccine: a nationwide study from Israel.
      ] mRBA-1273: 76–84% [
      • Tang P.
      • Hasan M.R.
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Khatib H.A.A.
      • et al.
      BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the Delta (B.1.617.2) variant in Qatar.
      ,
      • Puranik A.
      • Lenehan P.J.
      • Silvert E.
      • Niesen M.J.M.
      • Corchado-Garcia J.
      • O’Horo J.C.
      • et al.
      Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence.
      ]

      mRNA-vaccines: 64% [
      • Seppälä E.
      • Veneti L.
      • Starrfelt J.
      • Danielsen A.S.
      • Bragstad K.
      • Hungnes O.
      • et al.
      Vaccine effectiveness against infection with the delta (B.1.617.2) variant, Norway, April to August 2021.
      ]

      mRNA-vaccines/Janssen: 47–79% [
      • Rosenberg E.S.
      New COVID-19 cases and hospitalizations among adults, by vaccination status — New York, may 3–July 25, 2021.
      ,
      • Tartof S.Y.
      • Slezak J.M.
      • Fischer H.
      • Hong V.
      • Ackerson B.K.
      • Ranasinghe O.N.
      • et al.
      Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study.
      ]

      AZD1222: 60–67% [
      • Sheikh A.
      • McMenamin J.
      • Taylor B.
      • Robertson C.
      SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness.
      ,
      • Pouwels K.B.
      • Pritchard E.
      • Matthews P.C.
      • Stoesser N.
      • Eyre D.W.
      • Vihta K.-D.
      • et al.
      Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.
      ] mRNA/AZD-1222: 49% [
      • Elliott P.
      • Haw D.
      • Wang H.
      • Eales O.
      • Walters C.
      • Ainslie K.
      • et al.
      REACT-1 round 13 final report: exponential growth, high prevalence of SARS-CoV-2 and vaccine effectiveness associated with Delta variant in England during May to July.
      ]
      NA
      Effectiveness against COVID-19 hospitalization/death (fully vaccinated)BNT162b2n mRNA-1273: >89% [
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • Anis E.
      • Singer S.R.
      • Khan F.
      • et al.
      Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.
      ,
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ,
      • Bruxvoort K.
      • Sy L.S.
      • Qian L.
      • Ackerson B.K.
      • Luo Y.
      • Lee G.S.
      • et al.
      Real-world effectiveness of the mRNA-1273 vaccine against COVID-19: interim results from a prospective observational cohort study [Internet].
      ]
      BNT162b2: 95% [
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ]
      BNT162b2: 95% [
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ]
      BNT162b2: 80% [
      • Grannis S.J.
      Interim estimates of COVID-19 vaccine effectiveness against COVID-19–associated emergency department or urgent care clinic encounters and hospitalizations among adults during SARS-CoV-2 B.1.617.2 (delta) variant predominance — nine states, June–August 2021.
      ] mRNA-1273: 95% [
      • Grannis S.J.
      Interim estimates of COVID-19 vaccine effectiveness against COVID-19–associated emergency department or urgent care clinic encounters and hospitalizations among adults during SARS-CoV-2 B.1.617.2 (delta) variant predominance — nine states, June–August 2021.
      ]

      Ad26.COV1.S: 60–85% [
      • Grannis S.J.
      Interim estimates of COVID-19 vaccine effectiveness against COVID-19–associated emergency department or urgent care clinic encounters and hospitalizations among adults during SARS-CoV-2 B.1.617.2 (delta) variant predominance — nine states, June–August 2021.
      ,
      • Polinski J.M.
      • Weckstein A.R.
      • Batech M.
      • Kabelac C.
      • Kamath T.
      • Harvey R.
      • et al.
      Effectiveness of the single-dose Ad26.
      ] mRNA-vaccines: 95% [
      • Bruxvoort K.
      • Sy L.S.
      • Qian L.
      • Ackerson B.K.
      • Luo Y.
      • Lee G.S.
      • et al.
      Real-world effectiveness of the mRNA-1273 vaccine against COVID-19: interim results from a prospective observational cohort study [Internet].
      ,
      • Rosenberg E.S.
      New COVID-19 cases and hospitalizations among adults, by vaccination status — New York, may 3–July 25, 2021.
      ]
      NA
      SARS-CoV-2 variantsB.1.525P2P3B.1.526B.1.427B.1.429 CAL.20C
      EtaFormer ZetaFormer ThetaIotaFormer EpsilonFormer Epsilon
      Key spike mutationsQ52R, A67V, 69/70del, 144del, E484K, D614G, Q677H, F888LE484K, D614G, V1176F141/143del, E484K, N501Y, D614G, P681H, E1092K, H1101Y, V1176FL5F, T95I, D253G, D614G, A701V+(E484K or S477N)S13I, W152C, L452R, D614GS13I, W152C, L452R, D614G
      First detectionMultiple countries

      December 2020
      BrazilPhilippines

      January 2021
      USA

      December 2020
      USA

      September 2020
      USA

      September
      TransmissionNANANANA+18.6 to 24% in California [
      • Deng X.
      • Garcia-Knight M.A.
      • Khalid M.M.
      • Servellita V.
      • Wang C.
      • Morris M.K.
      • et al.
      Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation.
      ]
      +18.6 to 24% in California [
      • Deng X.
      • Garcia-Knight M.A.
      • Khalid M.M.
      • Servellita V.
      • Wang C.
      • Morris M.K.
      • et al.
      Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation.
      ]
      Risk of mortalityNANANANANANA
      Impact on post-vaccination sera (reduction in neutralization activity)NANANA0 to 3.6 fold reduction for BNT162b2 [
      • Annavajhala M.K.
      • Mohri H.
      • Wang P.
      • Zucker J.E.
      • Sheng Z.
      • Gomez-Simmonds A.
      • et al.
      A novel and expanding SARS-CoV-2 variant, B.1.526, identified in New York.
      ,
      • Carreño J.M.
      • Alshammary H.
      • Singh G.
      • Raskin A.
      • Amanat F.
      • Amoako A.
      • et al.
      Reduced neutralizing activity of post-SARS-CoV-2 vaccination serum against variants B.1.617.2, B.1.351, B.1.1.7+E484K and a sub-variant of C.37.
      ]

      1.4 to 3.3 fold reduction for mRNA-1273 [
      • Choi A.
      • Koch M.
      • Wu K.
      • Dixon G.
      • Oestreicher J.
      • Legault H.
      • et al.
      Serum neutralizing activity of mRNA-1273 against SARS-CoV-2 variants.
      ,
      • Annavajhala M.K.
      • Mohri H.
      • Wang P.
      • Zucker J.E.
      • Sheng Z.
      • Gomez-Simmonds A.
      • et al.
      A novel and expanding SARS-CoV-2 variant, B.1.526, identified in New York.
      ]

      4 fold reduction for CoronaVac [
      • Chen Y.
      • Shen H.
      • Huang R.
      • Tong X.
      • Wu C.
      Serum neutralising activity against SARS-CoV-2 variants elicited by CoronaVac.
      ]
      2.3 fold reduction for BNT162b2 [
      • Uriu K.
      • Kimura I.
      • Shirakawa K.
      • Takaori-Kondo A.
      • Nakada T.
      • Kaneda A.
      • et al.
      Ineffective neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine sera.
      ]
      1.3 to 4 fold reduction for BNT162b2 [
      • Deng X.
      • Garcia-Knight M.A.
      • Khalid M.M.
      • Servellita V.
      • Wang C.
      • Morris M.K.
      • et al.
      Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation.
      ,
      • McCallum M.
      • Bassi J.
      • Marco A.D.
      • Chen A.
      • Walls A.C.
      • Iulio J.D.
      • et al.
      SARS-CoV-2 immune evasion by variant B.1.427/B.1.429.
      ,
      • Liu Y.
      • Liu J.
      • Xia H.
      • Zhang X.
      • Zou J.
      • Fontes-Garfias C.R.
      • et al.
      BNT162b2-elicited neutralization against New SARS-CoV-2 spike variants.
      ]

      2 to 2.8 for mRNA-1273 [
      • Shen X.
      • Tang H.
      • Pajon R.
      • Smith G.
      • Glenn G.M.
      • Shi W.
      • et al.
      Neutralization of SARS-CoV-2 variants B.1.429 and B.1.351.
      ,
      • Choi A.
      • Koch M.
      • Wu K.
      • Dixon G.
      • Oestreicher J.
      • Legault H.
      • et al.
      Serum neutralizing activity of mRNA-1273 against SARS-CoV-2 variants.
      ,
      • McCallum M.
      • Bassi J.
      • Marco A.D.
      • Chen A.
      • Walls A.C.
      • Iulio J.D.
      • et al.
      SARS-CoV-2 immune evasion by variant B.1.427/B.1.429.
      ]

      2.5 fold reduction for NVX-CoV2373 [
      • Shen X.
      • Tang H.
      • Pajon R.
      • Smith G.
      • Glenn G.M.
      • Shi W.
      • et al.
      Neutralization of SARS-CoV-2 variants B.1.429 and B.1.351.
      ]

      1.3 fold reduction for CoronaVac [
      • Chen Y.
      • Shen H.
      • Huang R.
      • Tong X.
      • Wu C.
      Serum neutralising activity against SARS-CoV-2 variants elicited by CoronaVac.
      ]
      Effectiveness against infection (full vaccinated)NANANANANANA
      Effectiveness against hospitalization/death (full vaccinated)NANANANANANA
      SARS-CoV-2 variantsB.1.621C.37
      MuLambda
      Key spike mutationsR346K, E484K, N501Y, D614G, P681HL452Q, F490S, D614G
      First detectionColombia

      January 2021
      Peru

      December 2020
      TransmissionNANA
      Risk of mortalityNANA
      Impact on post-vaccination sera (reduction in neutralization activity)2–7.6-fold reduction for BNT162b2 [
      • Uriu K.
      • Kimura I.
      • Shirakawa K.
      • Takaori-Kondo A.
      • Nakada T.
      • Kaneda A.
      • et al.
      Ineffective neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine sera.
      ,
      • Messali S.
      • Bertelli A.
      • Campisi G.
      • Zani A.
      • Ciccozzi M.
      • Caruso A.
      • et al.
      A cluster of the new SARS-CoV-2 B.1.621 lineage in Italy and sensitivity of the viral isolate to the BNT162b2 vaccine.
      ]
      3.1-fold reduction for CoronaVac [
      • Acevedo M.L.
      • Alonso-Palomares L.
      • Bustamante A.
      • Gaggero A.
      • Paredes F.
      • Cortés C.P.
      • et al.
      Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda.
      ]

      1.7–4.6-fold reduction for BNT162b2 [
      • Uriu K.
      • Kimura I.
      • Shirakawa K.
      • Takaori-Kondo A.
      • Nakada T.
      • Kaneda A.
      • et al.
      Ineffective neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine sera.
      ,
      • Carreño J.M.
      • Alshammary H.
      • Singh G.
      • Raskin A.
      • Amanat F.
      • Amoako A.
      • et al.
      Reduced neutralizing activity of post-SARS-CoV-2 vaccination serum against variants B.1.617.2, B.1.351, B.1.1.7+E484K and a sub-variant of C.37.
      ,
      • Tada T.
      • Zhou H.
      • Dcosta B.M.
      • Samanovic M.I.
      • Mulligan M.J.
      • Landau N.R.
      SARS-CoV-2 Lambda variant remains susceptible to neutralization by mRNA vaccine-elicited antibodies and convalescent serum.
      ]

      3.3–4.6-fold reduction for mRNA-1273 [
      • Tada T.
      • Zhou H.
      • Dcosta B.M.
      • Samanovic M.I.
      • Mulligan M.J.
      • Landau N.R.
      SARS-CoV-2 Lambda variant remains susceptible to neutralization by mRNA vaccine-elicited antibodies and convalescent serum.
      ]

      2.9-fold reduction for Sputnik V [
      • Lopez Ledesma M.M.G.
      • Sanchez L.
      • Ojeda D.S.
      • Rouco S.O.
      • Rossi A.H.
      • Varese A.
      • et al.
      Temporal increase in neutralization potency of SARS-CoV-2 antibodies and reduced viral variant escape after Sputnik V vaccination.
      ]
      Effectiveness against infection (full vaccinated)NANA
      Effectiveness against hospitalization/death (full vaccinated)NANA
      NA, not available.
      Fig. 2
      Fig. 2Vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) asymptomatic or symptomatic infection from real-world studies (in % and 95%CI) according to the number of doses. Confidence intervals are delimited by the grey rectangular area.
      Fig. 3
      Fig. 3Vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hospitalization or death from real-world studies (in % and 95%CI) according to the number of doses. Confidence intervals are delimited by the grey rectangular area.
      Fig. 4
      Fig. 4Vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from real-world studies (in % and 95%CI) according to the number of doses. Confidence intervals are delimited by the grey rectangular area. Blue, orange, red, pale blue, green refer to Alpha, Beta, Delta, Gamma and unsequenced strains, respectively.
      Fig. 5
      Fig. 5Average fold reduction in neutralizing response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant versus wild type/D614G SARS-CoV-2 for each coronavirus disease 2019 (COVID-19) vaccine in 54 seroneutralization assays. The line in the middle of the box is the median. The box edges are the 25th and 75th percentiles. These boxplots included different methods assessing neutralizing antibody titres. Methods are detailed in the .

      Randomized clinical trials on vaccine efficacy

      In phase III trials (Table 2 and Fig. 1), all the main outcomes were efficacy against symptomatic infection after the second dose. In most trials, the strain was not sequenced.

       Messenger RNA (mRNA) vaccines

      mRNA-based drugs are new but not unknown. In 1990, the direct injection of mRNA in mouse muscle cells proved the feasibility of mRNA vaccines [
      • Wolff J.A.
      • Malone R.W.
      • Williams P.
      • Chong W.
      • Acsadi G.
      • Jani A.
      • et al.
      Direct gene transfer into mouse muscle in vivo.
      ]. mRNA instability, high innate immunogenicity and delivery issues were the main obstacles. BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 were the first authorized mRNA-based vaccines. They contain the mRNA of the antigen of interest which enters cells and is translated into the spike protein to induce an immune response. Against the historical strain, BNT162b2 and mRNA-1273 vaccines had an efficacy of >90% at 5–6 months' follow-up post second dose, whereas CVnCoV had a lower efficacy of 48%.

       Viral vector vaccines

      Viral vectors are delivery systems containing nucleic acid encoding an antigen. AZD1222, Ad5-nCoV and Sputnik V had an efficacy of 65–91.6% against the historical strain. AZD1222 had an efficacy of 70.4 against Alpha. Ad26.COV2.S had an efficacy of 69.4% in Brazil (mainly P2). AZD1222 and Ad26.COV2.S had efficacies of 10.4% and 64.7%, respectively, against Beta in South Africa.

       Inactivated and protein subunit vaccines

      Inactivated vaccines are whole viruses that cannot infect cells and replicate [
      • Plotkin S.
      History of vaccination.
      ]. Subunit vaccines are made of fragments of proteins or polysaccharides. NVX-COV2373 had an efficacy of 89–91.6% against the historical strain, 86.3–93.2% against Alpha and 60% against Beta. CoronaVac, BBIBP-CorV, Wuhan inactivated vaccine, Covaxin and Abdala had an efficacy of 50.6–92.3% but the SARS-CoV-2 strains were not specified. KoviVac, Barekatn QazVac, RBD-Dimer, EpiVacCorona had no phase III trial data published at the time of this review.Real world studies.
      Post-marketing surveillance studies results are summarized in Table 3 and detailed in Supplementary Material Table S2. Most studies have a follow-up of 90 days post-vaccination.

       Effectiveness against COVID-19 (symptomatic infection)

      After full immunization, mRNA vaccine effectiveness against disease was 88–100% against Alpha [
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • Anis E.
      • Singer S.R.
      • Khan F.
      • et al.
      Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.
      ,
      • Abu-Raddad L.J.
      • Chemaitelly H.
      • Butt A.A.
      Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants.
      ,
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ,
      • Bruxvoort K.
      • Sy L.S.
      • Qian L.
      • Ackerson B.K.
      • Luo Y.
      • Lee G.S.
      • et al.
      Real-world effectiveness of the mRNA-1273 vaccine against COVID-19: interim results from a prospective observational cohort study [Internet].
      ,
      • Charmet T.
      • Schaeffer L.
      • Grant R.
      • Galmiche S.
      • Chény O.
      • Von Platen C.
      • et al.
      Impact of original, B.1.1.7, and B.1.351/P.1 SARS-CoV-2 lineages on vaccine effectiveness of two doses of COVID-19 mRNA vaccines: results from a nationwide case-control study in France.
      ,
      • Bernal J.L.
      • Andrews N.
      • Gower C.
      • Robertson C.
      • Stowe J.
      • Tessier E.
      • et al.
      Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case–control study.
      ,
      • Paris C.
      • Perrin S.
      • Hamonic S.
      • Bourget B.
      • Roué C.
      • Brassard O.
      • et al.
      Effectiveness of mRNA-BNT162b2, mRNA-1273, and ChAdOx1 nCoV-19 vaccines against COVID-19 in health care workers: an observational study using surveillance data.
      ,
      • Dagan N.
      • Barda N.
      • Biron-Shental T.
      • Makov-Assif M.
      • Key C.
      • Kohane I.S.
      • et al.
      Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy.
      ], 76–100% against Beta/Gamma [
      • Abu-Raddad L.J.
      • Chemaitelly H.
      • Butt A.A.
      Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants.
      ,
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ,
      • Charmet T.
      • Schaeffer L.
      • Grant R.
      • Galmiche S.
      • Chény O.
      • Von Platen C.
      • et al.
      Impact of original, B.1.1.7, and B.1.351/P.1 SARS-CoV-2 lineages on vaccine effectiveness of two doses of COVID-19 mRNA vaccines: results from a nationwide case-control study in France.
      ], 47.3–88% against Delta [
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ,
      • Sheikh A.
      • McMenamin J.
      • Taylor B.
      • Robertson C.
      SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness.
      ,
      • Bernal J.L.
      • Andrews N.
      • Gower C.
      • Gallagher E.
      • Simmons R.
      • Thelwall S.
      • et al.
      Effectiveness of COVID-19 vaccines against the B.1.617.2 variant [Internet].
      ,
      • Keehner J.
      • Horton L.E.
      • Binkin N.J.
      • Laurent L.C.
      • Pride D.
      • Longhurst C.A.
      • et al.
      Resurgence of SARS-CoV-2 infection in a highly vaccinated health system workforce.
      ,
      • Andrews N.
      • Tessier E.
      • Stowe J.
      • Gower C.
      • Kirsebom F.
      • Simmons R.
      • et al.
      Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK.
      ], and 89–100% when SRAS-CoV-2 strain was not sequenced [
      • Charmet T.
      • Schaeffer L.
      • Grant R.
      • Galmiche S.
      • Chény O.
      • Von Platen C.
      • et al.
      Impact of original, B.1.1.7, and B.1.351/P.1 SARS-CoV-2 lineages on vaccine effectiveness of two doses of COVID-19 mRNA vaccines: results from a nationwide case-control study in France.
      ,
      • Bernal J.L.
      • Andrews N.
      • Gower C.
      • Robertson C.
      • Stowe J.
      • Tessier E.
      • et al.
      Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case–control study.
      ,
      • Dagan N.
      • Barda N.
      • Kepten E.
      • Miron O.
      • Perchik S.
      • Katz M.A.
      • et al.
      BNT162b2 mRNA Covid-19 vaccine in a Nationwide mass vaccination setting.
      ,
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Al Khatib H.A.
      • Tang P.
      • Hasan M.R.
      • et al.
      mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar.
      ,
      • Chodick G.
      • Tene L.
      • Rotem R.S.
      • Patalon T.
      • Gazit S.
      • Ben-Tov A.
      • et al.
      The effectiveness of the TWO-DOSE BNT162b2 vaccine: analysis of real-world data.
      ,
      • Fabiani M.
      • Ramigni M.
      • Gobbetto V.
      • Mateo-Urdiales A.
      • Pezzotti P.
      • Piovesan C.
      Effectiveness of the Comirnaty (BNT162b2, BioNTech/Pfizer) vaccine in preventing SARS-CoV-2 infection among healthcare workers, Treviso province, Veneto region, Italy, 27 December 2020 to 24 March 2021.
      ,
      • Angel Y.
      • Spitzer A.
      • Henig O.
      • Saiag E.
      • Sprecher E.
      • Padova H.
      • et al.
      Association between vaccination with BNT162b2 and incidence of symptomatic and asymptomatic SARS-CoV-2 infections among health care workers.
      ,
      • Pilishvili T.
      • Gierke R.
      • Fleming-Dutra K.E.
      • Farrar J.L.
      • Mohr N.M.
      • Talan D.A.
      • et al.
      Effectiveness of mRNA Covid-19 vaccine among U.S. health care personnel.
      ] (Fig. 2). AZD1222 effectiveness against disease was 74.5% against Alpha [
      • Bernal J.L.
      • Andrews N.
      • Gower C.
      • Gallagher E.
      • Simmons R.
      • Thelwall S.
      • et al.
      Effectiveness of COVID-19 vaccines against the B.1.617.2 variant [Internet].
      ] and 67% against Delta [
      • Sheikh A.
      • McMenamin J.
      • Taylor B.
      • Robertson C.
      SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness.
      ,
      • Andrews N.
      • Tessier E.
      • Stowe J.
      • Gower C.
      • Kirsebom F.
      • Simmons R.
      • et al.
      Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK.
      ] in the UK. CoronaVac effectiveness was 36.8–73.8% against Alpha/Gamma/D614G strain in Chile and Brazil [
      • Faria E de
      • Guedes A.R.
      • Oliveira M.S.
      • Moreira MV. de G.
      • Maia F.L.
      • Barboza A. dos S.
      • et al.
      Performance of vaccination with CoronaVac in a cohort of healthcare workers (HCW) - preliminary report.
      ,
      • Jara A.
      • Undurraga E.A.
      • González C.
      • Paredes F.
      • Fontecilla T.
      • Jara G.
      • et al.
      Effectiveness of an inactivated SARS-CoV-2 vaccine in Chile.
      ,
      • Hitchings M.D.T.
      • Ranzani O.T.
      • Torres M.S.S.
      • Oliveira SB de
      • Almiron M.
      • Said R.
      • et al.
      Effectiveness of CoronaVac among healthcare workers in the setting of high SARS-CoV-2 Gamma variant transmission in Manaus, Brazil: a test-negative case-control study.
      ]. CoronaVac or BBIBP-COrV administration was associated with an effectiveness of 59% in China [
      • Li X.-N.
      • Huang Y.
      • Wang W.
      • Jing Q.-L.
      • Zhang C.-H.
      • Qin P.-Z.
      • et al.
      Effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant infection in Guangzhou: a test-negative case–control real-world study.
      ].

       Effectiveness against COVID-19-related hospitalization and death

      After full immunization (Fig. 3), mRNA vaccine or AZD1222 effectiveness against hospitalization or death was over 87–94% [
      • Dagan N.
      • Barda N.
      • Kepten E.
      • Miron O.
      • Perchik S.
      • Katz M.A.
      • et al.
      BNT162b2 mRNA Covid-19 vaccine in a Nationwide mass vaccination setting.
      ,
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • Anis E.
      • Singer S.R.
      • Khan F.
      • et al.
      Nationwide vaccination campaign with BNT162b2 in Israel demonstrates high vaccine effectiveness and marked declines in incidence of SARS-CoV-2 infections and COVID-19 cases, hospitalizations, and deaths [Internet].
      ] when the strain was not sequenced, 89–95% against Alpha [
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • Anis E.
      • Singer S.R.
      • Khan F.
      • et al.
      Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.
      ,
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ,
      • Bruxvoort K.
      • Sy L.S.
      • Qian L.
      • Ackerson B.K.
      • Luo Y.
      • Lee G.S.
      • et al.
      Real-world effectiveness of the mRNA-1273 vaccine against COVID-19: interim results from a prospective observational cohort study [Internet].
      ], 95% against Beta/Gamma [
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ], 96% against Alpha/Delta [
      • Bruxvoort K.
      • Sy L.S.
      • Qian L.
      • Ackerson B.K.
      • Luo Y.
      • Lee G.S.
      • et al.
      Real-world effectiveness of the mRNA-1273 vaccine against COVID-19: interim results from a prospective observational cohort study [Internet].
      ], and 80–95% against Delta [
      • Rosenberg E.S.
      New COVID-19 cases and hospitalizations among adults, by vaccination status — New York, may 3–July 25, 2021.
      ,
      • Grannis S.J.
      Interim estimates of COVID-19 vaccine effectiveness against COVID-19–associated emergency department or urgent care clinic encounters and hospitalizations among adults during SARS-CoV-2 B.1.617.2 (delta) variant predominance — nine states, June–August 2021.
      ]. CoronaVac was very effective against hospitalization (87.5%) and mortality (86.3%) after full immunization [
      • Jara A.
      • Undurraga E.A.
      • González C.
      • Paredes F.
      • Fontecilla T.
      • Jara G.
      • et al.
      Effectiveness of an inactivated SARS-CoV-2 vaccine in Chile.
      ]. Ad26.COV1.S had an effectiveness of 60–85% against Delta [
      • Grannis S.J.
      Interim estimates of COVID-19 vaccine effectiveness against COVID-19–associated emergency department or urgent care clinic encounters and hospitalizations among adults during SARS-CoV-2 B.1.617.2 (delta) variant predominance — nine states, June–August 2021.
      ,
      • Polinski J.M.
      • Weckstein A.R.
      • Batech M.
      • Kabelac C.
      • Kamath T.
      • Harvey R.
      • et al.
      Effectiveness of the single-dose Ad26.
      ].
      Overall, the effectiveness of mRNA-vaccine and CoronaVac was reduced for Delta infection, but they still offered a high level of protection against severe COVID-19 and hospitalization for all variants after full immunization [
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • Anis E.
      • Singer S.R.
      • Khan F.
      • et al.
      Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.
      ,
      • Nasreen S.
      • He S.
      • Chung H.
      • Brown K.A.
      • Gubbay J.B.
      • Buchan S.A.
      • et al.
      Effectiveness of COVID-19 vaccines against variants of concern.
      ,
      • Bruxvoort K.
      • Sy L.S.
      • Qian L.
      • Ackerson B.K.
      • Luo Y.
      • Lee G.S.
      • et al.
      Real-world effectiveness of the mRNA-1273 vaccine against COVID-19: interim results from a prospective observational cohort study [Internet].
      ,
      • Dagan N.
      • Barda N.
      • Biron-Shental T.
      • Makov-Assif M.
      • Key C.
      • Kohane I.S.
      • et al.
      Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy.
      ,
      • Dagan N.
      • Barda N.
      • Kepten E.
      • Miron O.
      • Perchik S.
      • Katz M.A.
      • et al.
      BNT162b2 mRNA Covid-19 vaccine in a Nationwide mass vaccination setting.
      ,
      • Jara A.
      • Undurraga E.A.
      • González C.
      • Paredes F.
      • Fontecilla T.
      • Jara G.
      • et al.
      Effectiveness of an inactivated SARS-CoV-2 vaccine in Chile.
      ,
      • Rosenberg E.S.
      New COVID-19 cases and hospitalizations among adults, by vaccination status — New York, may 3–July 25, 2021.
      ,
      • Pawlowski C.
      • Lenehan P.
      • Puranik A.
      • Agarwal V.
      • Venkatakrishnan A.J.
      • Niesen M.J.M.
      • et al.
      FDA-authorized mRNA COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system.
      ,
      • Tenforde M.W.
      Effectiveness of pfizer-BioNTech and Moderna vaccines against COVID-19 among hospitalized adults aged ≥65 Years — United States, January–March 2021.
      ].

       Effectiveness against asymptomatic SARS-CoV-2 infection

      After full immunization, effectiveness was 90–92% for AZD1222 and BNT162b2 against unspecified strains [
      • Shah A.S.V.
      • Gribben C.
      • Bishop J.
      • Hanlon P.
      • Caldwell D.
      • Wood R.
      • et al.
      Effect of vaccination on transmission of SARS-CoV-2.
      ,
      • Lumley S.F.
      • Rodger G.
      • Constantinides B.
      • Sanderson N.
      • Chau K.K.
      • Street T.L.
      • et al.
      An observational cohort study on the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and B.1.1.7 variant infection in healthcare workers by antibody and vaccination status.
      ] (Fig. 4). For mRNA vaccines, effectiveness against infection was 89.5–99.2% against Alpha [
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • Anis E.
      • Singer S.R.
      • Khan F.
      • et al.
      Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.
      ,
      • Abu-Raddad L.J.
      • Chemaitelly H.
      • Butt A.A.
      Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants.
      ,
      • Dagan N.
      • Barda N.
      • Kepten E.
      • Miron O.
      • Perchik S.
      • Katz M.A.
      • et al.
      BNT162b2 mRNA Covid-19 vaccine in a Nationwide mass vaccination setting.
      ,
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Al Khatib H.A.
      • Tang P.
      • Hasan M.R.
      • et al.
      mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar.
      ,
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Al Khatib H.A.
      • Tang P.
      • Hasan M.R.
      • et al.
      mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar.
      ,
      • Pouwels K.B.
      • Pritchard E.
      • Matthews P.C.
      • Stoesser N.
      • Eyre D.W.
      • Vihta K.-D.
      • et al.
      Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.
      ], 75–96.4% against Beta [
      • Abu-Raddad L.J.
      • Chemaitelly H.
      • Butt A.A.
      Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants.
      ,
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Al Khatib H.A.
      • Tang P.
      • Hasan M.R.
      • et al.
      mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar.
      ], 42–84.4% against Delta [
      • Sheikh A.
      • McMenamin J.
      • Taylor B.
      • Robertson C.
      SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness.
      ,
      • Pouwels K.B.
      • Pritchard E.
      • Matthews P.C.
      • Stoesser N.
      • Eyre D.W.
      • Vihta K.-D.
      • et al.
      Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.
      ,
      • Tang P.
      • Hasan M.R.
      • Chemaitelly H.
      • Yassine H.M.
      • Benslimane F.M.
      • Khatib H.A.A.
      • et al.
      BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the Delta (B.1.617.2) variant in Qatar.
      ,
      • Puranik A.
      • Lenehan P.J.
      • Silvert E.
      • Niesen M.J.M.
      • Corchado-Garcia J.
      • O’Horo J.C.
      • et al.
      Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence.
      ,
      • Goldberg Y.
      • Mandel M.
      • Bar-On Y.M.
      • Bodenheimer O.
      • Freedman L.
      • Haas E.J.
      • et al.
      Waning immunity of the BNT162b2 vaccine: a nationwide study from Israel.
      ] and 80–98.2% against unspecified strains [
      • Dagan N.
      • Barda N.
      • Kepten E.
      • Miron O.
      • Perchik S.
      • Katz M.A.
      • et al.
      BNT162b2 mRNA Covid-19 vaccine in a Nationwide mass vaccination setting.
      ,
      • Chodick G.
      • Tene L.
      • Rotem R.S.
      • Patalon T.
      • Gazit S.
      • Ben-Tov A.
      • et al.
      The effectiveness of the TWO-DOSE BNT162b2 vaccine: analysis of real-world data.
      ,
      • Fabiani M.
      • Ramigni M.
      • Gobbetto V.
      • Mateo-Urdiales A.
      • Pezzotti P.
      • Piovesan C.
      Effectiveness of the Comirnaty (BNT162b2, BioNTech/Pfizer) vaccine in preventing SARS-CoV-2 infection among healthcare workers, Treviso province, Veneto region, Italy, 27 December 2020 to 24 March 2021.
      ,
      • Pawlowski C.
      • Lenehan P.
      • Puranik A.
      • Agarwal V.
      • Venkatakrishnan A.J.
      • Niesen M.J.M.
      • et al.
      FDA-authorized mRNA COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system.
      ,
      • Thompson M.G.
      • Burgess J.L.
      • Naleway A.L.
      • Tyner H.L.
      • Yoon S.K.
      • Meece J.
      • et al.
      Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers — eight U.S. Locations, December 2020–March 2021.
      ,
      • Bianchi F.P.
      • Germinario C.A.
      • Migliore G.
      • Vimercati L.
      • Martinelli A.
      • Lobifaro A.
      • et al.
      BNT162b2 mRNA Covid-19 vaccine effectiveness in the prevention of SARS-CoV-2 infection: a preliminary report.
      ,
      • Hall V.J.
      • Foulkes S.
      • Saei A.
      • Andrews N.
      • Oguti B.
      • Charlett A.
      • et al.
      Effectiveness of BNT162b2 mRNA vaccine against infection and COVID-19 vaccine coverage in healthcare workers in England, multicentre prospective cohort study (the SIREN Study).
      ,
      • Heymann A.D.
      • Zacay G.
      • Shasha D.
      • Bareket R.
      • Kadim I.
      • Sikron F.H.
      • et al.
      BNT162b2 vaccine effectiveness in preventing asymptomatic infection with SARS-CoV-2 virus: a nationwide historical cohort study.
      ,
      • Moustsen-Helms I.R.
      • Emborg H.-D.
      • Nielsen J.
      • Nielsen K.F.
      • Krause T.G.
      • Mølbak K.
      • et al.
      Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 vaccine in long-term care facility residents and healthcare workers – a Danish cohort study.
      ,
      • Tang L.
      • Hijano D.R.
      • Gaur A.H.
      • Geiger T.L.
      • Neufeld E.J.
      • Hoffman J.M.
      • et al.
      Asymptomatic and symptomatic SARS-CoV-2 infections after BNT162b2 vaccination in a routinely screened workforce.
      ,
      • Tande A.J.
      • Pollock B.D.
      • Shah N.D.
      • Farrugia G.
      • Virk A.
      • Swift M.
      • et al.
      Impact of the COVID-19 Vaccine on asymptomatic infection among patients undergoing pre-procedural COVID-19 molecular screening.
      ,
      • Butt A.A.
      • Omer S.B.
      • Yan P.
      • Shaikh O.S.
      • Mayr F.B.
      SARS-CoV-2 vaccine effectiveness in a high-risk national population in a real-world setting.
      ,
      • Andrejko K.L.
      • Pry J.
      • Myers J.F.
      • Jewell N.P.
      • Openshaw J.
      • Watt J.
      • et al.
      Prevention of COVID-19 by mRNA-based vaccines within the general population of California.
      ]. AZD1222 had an effectiveness of 49–67% in the UK [
      • Sheikh A.
      • McMenamin J.
      • Taylor B.
      • Robertson C.
      SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness.
      ,
      • Pouwels K.B.
      • Pritchard E.
      • Matthews P.C.
      • Stoesser N.
      • Eyre D.W.
      • Vihta K.-D.
      • et al.
      Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK.
      ,
      • Elliott P.
      • Haw D.
      • Wang H.
      • Eales O.
      • Walters C.
      • Ainslie K.
      • et al.
      REACT-1 round 13 final report: exponential growth, high prevalence of SARS-CoV-2 and vaccine effectiveness associated with Delta variant in England during May to July.
      ]. mRNA vaccines and Ad26.COV2.S vaccines in the USA had an effectiveness of 47–80% against Delta [
      • Rosenberg E.S.
      New COVID-19 cases and hospitalizations among adults, by vaccination status — New York, may 3–July 25, 2021.
      ,
      • Fowlkes A.
      • Gaglani M.
      • Groover K.
      • Thiese M.S.
      • Tyner H.
      • Ellingson K.
      • et al.
      Effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infection among frontline workers before and during B.1.617.2 (Delta) variant predominance — eight U.S. locations, December 2020–August 2021.
      ,
      • Tartof S.Y.
      • Slezak J.M.
      • Fischer H.
      • Hong V.
      • Ackerson B.K.
      • Ranasinghe O.N.
      • et al.
      Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study.
      ]. Among pregnant women, a single dose or two doses led to an effectiveness of 78% against the original strain and 96% against Alpha, respectively. These previous studies focused on ≤6 years in people, but a retrospective cohort of teenagers aged 12–15 years in Israel also reported a high effectiveness of 91.5% against Delta infections [
      • Glatman-Freedman A.
      • Hershkovitz Y.
      • Kaufman Z.
      • Dichtiar R.
      • Keinan-Boker L.
      • Bromberg M.
      Early release—effectiveness of BNT162b2 vaccine in adolescents during outbreak of SARS-CoV-2 Delta variant infection, Israel, 2021.
      ].

       Impact on viral load, infectivity, transmission and long COVID

      Before Delta propagation, mRNA vaccines were associated with a lower viral load and a reduced duration of illness [
      • Thompson M.G.
      • Burgess J.L.
      • Naleway A.L.
      • Tyner H.
      • Yoon S.K.
      • Meece J.
      • et al.
      Prevention and attenuation of covid-19 with the BNT162b2 and mRNA-1273 vaccines.
      ,
      • Levine-Tiefenbrun M.
      • Yelin I.
      • Katz R.
      • Herzel E.
      • Golan Z.
      • Schreiber L.
      • et al.
      Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine.
      ]. Against Delta, surveillance studies in the US found both vaccinated and unvaccinated people had similarly low cycle threshold (Ct) values, indicating high viral load [
      • Griffin J.B.
      SARS-CoV-2 infections and hospitalizations among persons aged ≥16 years, by vaccination status — Los Angeles County, California, May 1–July 25, 2021.
      ,
      • Brown C.M.
      Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings — Barnstable County, Massachusetts, July 2021.
      ]. However, the large UK REACT-1 study—using random sampling and including participants who tested positive without showing symptoms—showed that vaccinated people had a lower viral load on average [
      • Elliott P.
      • Haw D.
      • Wang H.
      • Eales O.
      • Walters C.
      • Ainslie K.
      • et al.
      REACT-1 round 13 final report: exponential growth, high prevalence of SARS-CoV-2 and vaccine effectiveness associated with Delta variant in England during May to July.
      ]. A preprint in Singapore found that BNT162b2 vaccination was associated with a faster decline in viral loads among vaccinated people [
      • Chia P.Y.
      • Ong S.W.X.
      • Chiew C.J.
      • Ang L.W.
      • Chavatte J.-M.
      • Mak T.-M.
      • et al.
      Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine-breakthrough infections: a multi-center cohort study.
      ]. Ad26.COV2.S and BNT162b2 vaccines were associated with a lower probability of viral culture positivity, suggesting less shedding of infectious Delta virus in vaccinated people [
      • Shamier M.C.
      • Tostmann A.
      • Bogers S.
      • de Wilde J.
      • IJpelaar J.
      • van der Kleij W.A.
      • et al.
      Virological characteristics of SARS-CoV-2 vaccine breakthrough infections in health care workers.
      ]. Before the spread of Delta, a study in England reported a reduced transmission associated with BNT162b2 or AZD1222 vaccines in a household setting [
      • Harris R.J.
      • Hall J.A.
      • Zaidi A.
      • Andrews N.J.
      • Dunbar J.K.
      • Dabrera G.
      Effect of vaccination on household transmission of SARS-CoV-2 in England.
      ], and two other preliminary analyses confirmed these results [
      • Prunas O.
      • Warren J.L.
      • Crawford F.W.
      • Gazit S.
      • Patalon T.
      • Weinberger D.M.
      • et al.
      Vaccination with BNT162b2 reduces transmission of SARS-CoV-2 to household contacts in Israel.
      ,
      • Salazar P.M.D.
      • Link N.
      • Lamarca K.
      • Santillana M.
      High coverage COVID-19 mRNA vaccination rapidly controls SARS-CoV-2 transmission in long-term care facilities.
      ]. A Chinese preprint analysed infections among 5153 participants with 73 close-contact COVID-19 cases and observed a higher infection risk among unvaccinated or partially vaccinated participants (versus two doses of inactivated vaccines) [
      • Kang M.
      • Xin H.
      • Yuan J.
      • Ali S.T.
      • Liang Z.
      • Zhang J.
      • et al.
      Transmission dynamics and epidemiological characteristics of Delta variant infections in China.
      ]. In a large nested case–control study from the UK, participants with one or two vaccine doses reported having fewer symptoms and lower odds of having long COVID (symptoms over 28 days, OR =0.51 (95%CI: 0.32 to 0.82, after two doses) [
      • Antonelli M.
      • Penfold R.S.
      • Merino J.
      • Sudre C.H.
      • Molteni E.
      • Berry S.
      • et al.
      Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study.
      ].

       Waning immunity

      Several studies have suggested that the levels of antibodies after BNT162b2, mRNA-1273 and Ad26.COV2.S vaccines could last for at least 6 months but decrease over time thereafter [
      • Barouch D.H.
      • Stephenson K.E.
      • Sadoff J.
      • Yu J.
      • Chang A.
      • Gebre M.
      • et al.
      Durable humoral and cellular immune responses following Ad26.
      ,
      • Doria-Rose N.
      • Suthar M.S.
      • Makowski M.
      • O’Connell S.
      • McDermott A.B.
      • Flach B.
      • et al.
      Antibody persistence through 6 months after the second dose of mRNA-1273 vaccine for Covid-19.
      ,
      • Naaber P.
      • Tserel L.
      • Kangro K.
      • Sepp E.
      • Jürjenson V.
      • Adamson A.
      • et al.
      Dynamics of antibody response to BNT162b2 vaccine after six months: a longitudinal prospective study.
      ,
      • Pegu A.
      • O’Connell S.
      • Schmidt S.D.
      • O’Dell S.
      • Talana C.A.
      • Lai L.
      • et al.
      Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants.
      ]. For mRNA-1273, at 6 months neutralizing activity was maintained against Alpha, Gamma, Delta, Epsilon, whereas neutralizing activity was considerably decreased against Beta for half the participants [
      • Pegu A.
      • O’Connell S.
      • Schmidt S.D.
      • O’Dell S.
      • Talana C.A.
      • Lai L.
      • et al.
      Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants.
      ].
      Observational studies stratified by time since vaccination identified a decreasing effectiveness at 4–6 months (42–57%) for mRNA vaccines and 47.3% for AZD1222 against Delta infection [
      • Andrews N.
      • Tessier E.
      • Stowe J.
      • Gower C.
      • Kirsebom F.
      • Simmons R.
      • et al.
      Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK.
      ,
      • Puranik A.
      • Lenehan P.J.
      • Silvert E.
      • Niesen M.J.M.
      • Corchado-Garcia J.
      • O’Horo J.C.
      • et al.
      Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence.
      ,
      • Goldberg Y.
      • Mandel M.
      • Bar-On Y.M.
      • Bodenheimer O.
      • Freedman L.
      • Haas E.J.
      • et al.
      Waning immunity of the BNT162b2 vaccine: a nationwide study from Israel.
      ,
      • Tartof S.Y.
      • Slezak J.M.
      • Fischer H.
      • Hong V.
      • Ackerson B.K.
      • Ranasinghe O.N.
      • et al.
      Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study.
      ]. In the USA, effectiveness of mRNA vaccines against symptomatic infection fell from 94.3% in June to 65.5% in July 2021. The effectiveness against hospitalization remained high (>85%) for mRNA-1273 (92%), BNT162b2 (77–93%) and AZD-1222 (70.3%) at 4–6 months after full vaccination [
      • Andrews N.
      • Tessier E.
      • Stowe J.
      • Gower C.
      • Kirsebom F.
      • Simmons R.
      • et al.
      Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK.
      ,
      • Goldberg Y.
      • Mandel M.
      • Bar-On Y.M.
      • Bodenheimer O.
      • Freedman L.
      • Haas E.J.
      • et al.
      Waning immunity of the BNT162b2 vaccine: a nationwide study from Israel.
      ,
      • Tartof S.Y.
      • Slezak J.M.
      • Fischer H.
      • Hong V.
      • Ackerson B.K.
      • Ranasinghe O.N.
      • et al.
      Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study.
      ,
      • Self W.H.
      Comparative effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) vaccines in preventing COVID-19 hospitalizations among adults without immunocompromising conditions — United States, March–August 2021.
      ] and 68% at >28 days after full immunization for Ad26.COV2.S [
      • Self W.H.
      Comparative effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) vaccines in preventing COVID-19 hospitalizations among adults without immunocompromising conditions — United States, March–August 2021.
      ]. It is difficult to know whether the reduction in effectiveness against Delta infection is due to waning immunity over time or/and variants escaping immunity and/or increasing in collective immunity.

      Neutralization assays with variants of concern and variants of interest

      Mutations and variations occur in the SARS-CoV-2 virus due to evolution and adaptation processes [
      • van Dorp L.
      • Richard D.
      • Tan C.C.S.
      • Shaw L.P.
      • Acman M.
      • Balloux F.
      No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2.
      ]. Some SARS-CoV-2 variants of concern with mutations in the spike protein have an increased transmissibility [
      • Volz E.
      • Mishra S.
      • Chand M.
      • Barrett J.C.
      • Johnson R.
      • Geidelberg L.
      • et al.
      Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: insights from linking epidemiological and genetic data.
      ,
      • Tegally H.
      • Wilkinson E.
      • Giovanetti M.
      • Iranzadeh A.
      • Fonseca V.
      • Giandhari J.
      • et al.
      Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa.
      ,
      • Davies N.G.
      • Abbott S.
      • Barnard R.C.
      • Jarvis C.I.
      • Kucharski A.J.
      • Munday J.D.
      • et al.
      Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England.
      ,
      Public Health England
      SARS-CoV-2 variants of concern and variants under investigation.
      ,
      • Campbell F.
      • Archer B.
      • Laurenson-Schafer H.
      • Jinnai Y.
      • Konings F.
      • Batra N.
      • et al.
      Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021.
      ,
      ], which may be explained by an enhanced spike-protein-binding affinity for the ACE2 receptor. For example, Alpha and Beta have been shown to have a 1.98x and 4.62x greater binding affinity than original strain [
      • Ramanathan M.
      • Ferguson I.D.
      • Miao W.
      • Khavari P.A.
      SARS-CoV-2 B.1.1.7 and B.1.351 spike variants bind human ACE2 with increased affinity.
      ]. These variants may cause more severe disease [
      • Davies N.G.
      • Jarvis C.I.
      • Edmunds W.J.
      • Jewell N.P.
      • Diaz-Ordaz K.
      • Keogh R.H.
      Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7.
      ] and/or have a potential ability to escape the host or vaccine-induced immune response [
      • Planas D.
      • Bruel T.
      • Grzelak L.
      • Guivel-Benhassine F.
      • Staropoli I.
      • Porrot F.
      • et al.
      Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies.
      ,
      • Cele S.
      • Gazy I.
      • Jackson L.
      • Hwa S.-H.
      • Tegally H.
      • Lustig G.
      • et al.
      Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma.
      ]. Results from several seroneutralization assays assessing the neutralizing response of vaccine-induced antibodies are described in Fig. 5 and in Supplementary Material Table S3. In general, Alpha had a minimal impact on neutralization activity of antibodies by post-vaccination sera (Table 3). Neutralization was further reduced for variants with mutation E484K and Gamma. Beta had the highest reduction in neutralizing titres. Data were lacking for C.1.2 identified in South Africa in May 2021, but C.1.2 had a 1.7-fold higher substitution rate than the current global substitution rate [
      • Scheepers C.
      • Everatt J.
      • Amoako D.G.
      • Mnguni A.
      • Ismail A.
      • Mahlangu B.
      • et al.
      The continuous evolution of SARS-CoV-2 in South Africa: a new lineage with rapid accumulation of mutations of concern and global detection.
      ].

       Limitations of neutralizing assays

      Limitations concerning neutralizing assays should be emphasised. First, most studies were preprints. Second, results are not necessarily linked to clinical consequences. However, one study based on seven vaccines reported a high correlation between neutralization titres and protection estimated in phase III trials [
      • Khoury D.S.
      • Cromer D.
      • Reynaldi A.
      • Schlub T.E.
      • Wheatley A.K.
      • Juno J.A.
      • et al.
      Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.
      ]. A 50% protection against SARS-CoV-2 infection corresponded to a neutralization level of 20.2% of the mean convalescent level. Third, the methods of the studies varied (pseudovirus assay, plaque reduction neutralization testing, microneutralization assay, focus reduction neutralization test). We included 28 pseudovirus assays and 26 live virus assays. Pseudovirus assays approximate authentic SARS-CoV-2 neutralization and only evaluate neutralizing antibodies on pseudoviruses with mutations in the spike protein. Additionally, the choice of cell lines and virus models (vesicular stomatitis virus or human immunodeficiency virus-1 for example) can impact the neutralizing activity. Pseudoviruses are surrogates and cannot complete the same life cycle as the live virus, thus it is not possible to assess the inhibitory effect on viral replication, but they are used to study virus entry into cells. Live virus neutralization assay remains the reference standard, but it needs a higher safety level (a biosafety level 3 laboratory). Fourth, the time post-vaccination and study populations were not always comparable regarding age or COVID-19 history. Fifth, T-cell responses were not assessed. Most studies on in vitro vaccine efficacy focused on the ability of the vaccine antibodies to bind to the virus, which partially reflect vaccine effectiveness, but cell-mediated immunity should also be considered. Studies have shown that BNT162b2 and Ad26.COV2.S induce CD4+ and CD8+ T-cell responses [
      • Barouch D.H.
      • Stephenson K.E.
      • Sadoff J.
      • Yu J.
      • Chang A.
      • Gebre M.
      • et al.
      Durable humoral and cellular immune responses following Ad26.
      ,
      • Sahin U.
      • Muik A.
      • Vogler I.
      • Derhovanessian E.
      • Kranz L.M.
      • Vormehr M.
      • et al.
      BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans.
      ]. Preliminary reports have identified vaccine-induced CD4+ T cells 6 months after the second dose of RNA-1273 [
      • Mateus J.
      • Dan J.M.
      • Zhang Z.
      • Moderbacher C.R.
      • Lammers M.
      • Goodwin B.
      • et al.
      Low dose mRNA-1273 COVID-19 vaccine generates durable T cell memory and antibodies enhanced by pre-existing crossreactive T cell memory.
      ] and memory B cells at 6 months after two doses of BNT162b2 [
      • Ciabattini A.
      • Pastore G.
      • Fiorino F.
      • Polvere J.
      • Lucchesi S.
      • Pettini E.
      • et al.
      Evidence of SARS-Cov-2-specific memory B cells six months after vaccination with BNT162b2 mRNA vaccine.
      ]. SARS-CoV-2-specific memory T cells and B cells are important for long-term protection. A main limitation of these studies on cell-mediated immunity is small sample size.

      Vaccine regimens

       Heterologous prime-boost vaccination

      Changing recommendations for young people regarding use of AZD1222 and the need to accelerate the vaccination campaign has led some countries to advise heterologous prime-boost vaccination with a second dose of mRNA vaccines. An RCT conducted in the UK indicated an increase in systemic reactogenicity in a heterologous vaccination context versus homologous vaccination [
      • Shaw R.H.
      • Stuart A.
      • Greenland M.
      • Liu X.
      • Van-Tam J.S.N.
      • Snape M.D.
      Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data.
      ], but efficacy data have not yet been published. A press communication from El Instituto de Salud Carlos III from a phase II trial in Spain showed that the combination of AZD1222 and BNT162b2 induced a strong humoral response when compared to no second dose [
      El Institutot de Salud Carlos III
      Un ensayo clínico evaluará una segunda dosis de la vacuna de Pfizer en personas ya vacunadas con una dosis de AstraZeneca.
      ]. The Com-Cov randomized trial also supported flexibility in the use of AZD1222 and BNT162b2 with a 28-day interval inducing similar levels of SARS-CoV-2 anti-spike IgG [
      • Liu X.
      • Shaw R.H.
      • Stuart A.S.V.
      • Greenland M.
      • Aley P.K.
      • Andrews N.J.
      • et al.
      Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.
      ]. A preliminary study in Thailand observed an increase in neutralizing antibodies against Delta after a third dose of BNT162b2 or AZD1222 among participants who received two doses of CoronaVac [
      • Patamatamkul S.
      • Buranrat B.
      • Thammawat S.
      Induction of robust neutralizing antibodies against the COVID-19 Delta variant with ChAdOx1 nCoV-19 or BNT162b2 as a booster following a primary vaccination series with CoronaVac.
      ].

       Extension of the dose interval

      More generally, evidence on the extension of the interval between doses is scarce. Trials for AZD1222 showed that a longer delay was better, but for mRNA and other vaccines trials did not test different dose gaps [
      • Voysey M.
      • Clemens S.A.C.
      • Madhi S.A.
      • Weckx L.Y.
      • Folegatti P.M.
      • Aley P.K.
      • et al.
      Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.
      ]. A preprint reported that extending the interval to 6 weeks for BNT162b2 vaccine led to higher titres in neutralizing antibodies and a sustained T-cell response against the variants of concern [
      • Tauzin A.
      • Gong S.Y.
      • Beaudoin-Bussieres G.
      • Vezina D.
      • Gasser R.
      • Nault L.
      • et al.
      Strong humoral immune responses against SARS-CoV-2 Spike after BNT162b2 mRNA vaccination with a sixteen-week interval between doses.
      ]. Another analysis found that a second dose at 12 weeks induced a stronger humoral response than at a 3-week interval among older people [
      • Parry H.
      • Bruton R.
      • Stephens C.
      • Brown K.
      • Amirthalingam G.
      • Hallis B.
      • et al.
      Extended interval BNT162b2 vaccination enhances peak antibody generation in older people.
      ].

       A booster dose for specific populations

      Immunogenicity studies amongst transplant patients and patients with cancer showed a poor antibody response after a single dose or two doses of Pfizer vaccine [
      • Monin L.
      • Laing A.G.
      • Muñoz-Ruiz M.
      • McKenzie D.R.
      • Barrio I del M del
      • Alaguthurai T.
      • et al.
      Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.
      ,
      • Boyarsky B.J.
      • Werbel W.A.
      • Avery R.K.
      • Tobian A.A.R.
      • Massie A.B.
      • Segev D.L.
      • et al.
      Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients.
      ,
      • Palich R.
      • Veyri M.
      • Vozy A.
      • Marot S.
      • Gligorov J.
      • Benderra M.-A.
      • et al.
      High seroconversion rate but low antibody titers after two injections of BNT162b2 (Pfizer-BioNTech) vaccine in patients treated with chemotherapy for solid cancers.
      ]. Facing this issue, French, German, British and US health authorities have recommended a third dose for immunocompromised people and transplant recipients. A randomized trial in transplant recipients showed that a third dose of mRNA-1273 was safe, and 26 out of 59 participants who had negative antibody responses prior to the booster developed antibody responses after the third dose [
      • Hall V.G.
      • Ferreira V.H.
      • Ku T.
      • Ierullo M.
      • Majchrzak-Kita B.
      • Chaparro C.
      • et al.
      Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients.
      ]. However, this study did not look at the cellular immune response. Another study found that an additional dose of mRNA-1273 induced a serological response among 50% of kidney transplant recipients who hadn't responded after two doses [
      • Benotmane I.
      • Gautier G.
      • Perrin P.
      • Olagne J.
      • Cognard N.
      • Fafi-Kremer S.
      • et al.
      Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses.
      ]. A case–control study in preprint found an effectiveness against SARS-CoV-2 infection 14–20 days after the third dose increased by 79% (versus the second dose) [
      • Patalon T.
      • Gazit S.
      • Pitzer V.E.
      • Prunas O.
      • Warren J.L.
      • Weinberger D.M.
      Short term reduction in the odds of testing positive for SARS-CoV-2; a comparison between two doses and three doses of the BNT162b2 vaccine.
      ]. Another observational study in Israel found that a booster dose reduced the rate of confirmed infections and severe disease by a factor of 11.3 and 19.5, respectively, among elderly participants [
      • Bar-On Y.M.
      • Goldberg Y.
      • Mandel M.
      • Bodenheimer O.
      • Freedman L.
      • Kalkstein N.
      • et al.
      Protection of BNT162b2 vaccine booster against Covid-19 in Israel.
      ]. Two studies also showed that Moderna boosters (at least 6 months after the second dose) and Pfizer booster (8–11 months after the second dose) induced a strong humoral response against Beta [
      • Falsey A.R.
      • Frenck R.W.
      • Walsh E.E.
      • Kitchin N.
      • Absalon J.
      • Gurtman A.
      • et al.
      SARS-CoV-2 neutralization with BNT162b2 vaccine dose 3.
      ] and other variants of concern [
      • Choi A.
      • Koch M.
      • Wu K.
      • Chu L.
      • Ma L.
      • Hill A.
      • et al.
      Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis.
      ]. The expected local and systemic adverse events were mild and moderate and similar to those after the second dose.

       Vaccination of previously infected individuals

      Several neutralization assays have suggested that a single dose of BNT16b or mRNA-1273 among previously infected subjects could boost the cross-neutralization response against emerging variants such as Alpha, Beta or Gamma [
      • Lustig Y.
      • Nemet I.
      • Kliker L.
      • Zuckerman N.
      • Yishai R.
      • Alroy-Preis S.
      • et al.
      Neutralizing response against variants after SARS-CoV-2 infection and one dose of BNT162b2.
      ,
      • Stamatatos L.
      • Czartoski J.
      • Wan Y.-H.
      • Homad L.J.
      • Rubin V.
      • Glantz H.
      • et al.
      mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection.
      ]. These studies have demonstrated the potential benefits of vaccinating both non-infected and previously infected people. Finally, several studies have suggested that a single dose of mRNA vaccine may be sufficient to boost the antibody response in previously infected subjects and that the benefit of the second dose may be small [
      • Krammer F.
      • Srivastava K.
      • Alshammary H.
      • Amoako A.A.
      • Awawda M.H.
      • Beach K.F.
      • et al.
      Antibody responses in seropositive persons after a single dose of SARS-CoV-2 mRNA vaccine.
      ,
      • Anichini G.
      • Terrosi C.
      • Gandolfo C.
      • Gori Savellini G.
      • Fabrizi S.
      • Miceli G.B.
      • et al.
      SARS-CoV-2 antibody response in persons with past natural infection.
      ,
      • Goel R.R.
      • Apostolidis S.A.
      • Painter M.M.
      • Mathew D.
      • Pattekar A.
      • Kuthuru O.
      • et al.
      Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination.
      ,
      • Samanovic M.I.
      • Cornelius A.R.
      • Wilson J.P.
      • Karmacharya T.
      • Gray-Gaillard S.L.
      • Allen J.R.
      • et al.
      Poor antigen-specific responses to the second BNT162b2 mRNA vaccine dose in SARS-CoV-2-experienced individuals.
      ,
      • Saadat S.
      • Tehrani Z.R.
      • Logue J.
      • Newman M.
      • Frieman M.B.
      • Harris A.D.
      • et al.
      Single dose vaccination in healthcare workers previously infected with SARS-CoV-2.
      ].

      Severe adverse events

      The main severe adverse events reported in pharmacovigilance systems and post-authorization studies are summarized in Table 4. Among adults, the main severe adverse events reported were very rare: anaphylaxis (2.5–4.8 cases per million doses among adults) and myocarditis (6–27 cases per million) for mRNA vaccines; thrombosis with thrombocytopenia syndrome for the Janssen vaccine (three cases per million) and AstraZeneca vaccine (two cases per million), and Guillain–Barré syndrome (GBS) (7.8 cases per million) for the Janssen vaccine. For AZD1222, capillary leak syndrome was also identified as a possible adverse effect, and multisystem inflammatory syndrome is under investigation. The EMA excluded an association between AZD1222 and menstrual disorders [].
      Table 4Main severe adverse events following coronavirus disease 2019 (COVID-19) vaccination in observational studies and pharmacovigilance systems
      VaccineSerious adverse eventsCases per million doses administeredCountryAgeFollow-upNumber of participants or doses studiedReferences
      BNT162b2Anaphylaxis4.8/millionUSA≥12 years14th December 2020 to 26th June 202111.8 million doses administered (57% BNT162b2) to 6.2 million individualsKlein et al. [
      • Klein N.P.
      • Lewis N.
      • Goddard K.
      • Fireman B.
      • Zerbo O.
      • Hanson K.E.
      • et al.
      Surveillance for adverse events after COVID-19 mRNA vaccination.
      ]
      Anaphylaxis + anaphylactoid reactions476 cases among 40 million dosesUK≥16 years9th December 2020 to 1st September 202140 million doses (1 and 2)MHRA (Yellow Card Scheme) [
      • Medicines & Healthcare products Regulatory Agency
      ]
      Myocarditis

      Lymphadenopathy

      Appendicitis

      Herpes zoster infection
      2.7/100 000

      78.4/100 000

      5/100 000

      15.8/100 000
      Israel≥16 years20th December 2020 to 24th May 20211 736 832 participants (884 828 vaccinated)Barda et al. [
      • Barda N.
      • Dagan N.
      • Ben-Shlomo Y.
      • Kepten E.
      • Waxman J.
      • Ohana R.
      • et al.
      Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting.
      ]
      Bell's palsy

      Myocarditis/Pericarditis

      Transverse myelitis
      2.6/100 000

      0.86/100 000

      0.01/100 000
      Hongkong≥12 yearsUp to 31st August4 776 700 dosesHongkong Drug Office [
      Hong Kong Drug Office
      Safety Monitoring of COVID-19 Vaccines in Hong Kong [Internet].
      ]
      Myocarditis

      Pericarditis
      6/million

      4.9/million
      UK≥16 years9th December 2020 to 1st September 202140 million doses (1 and 2)MHRA (Yellow Card Scheme) [
      • Medicines & Healthcare products Regulatory Agency
      ]
      mRNA-1273Anaphylaxis5.1/millionUSA≥12 years14th December 2020, to 26th June 202111.8 million doses administered (43% mRNA-1273) to 6.2 million individualsKlein et al. [
      • Klein N.P.
      • Lewis N.
      • Goddard K.
      • Fireman B.
      • Zerbo O.
      • Hanson K.E.
      • et al.
      Surveillance for adverse events after COVID-19 mRNA vaccination.
      ]
      2.5/millionUSA≥16 years21st December 2020 to 10th January 20214 041 396 dosesUS CDC [
      CDCMMWR
      Allergic Reactions including anaphylaxis After receipt of the first dose of Moderna COVID-19 vaccine — United States, december 21, 2020–January 10, 2021.
      ]
      Myocarditis

      Pericarditis
      20.4/million

      14.8/million
      UK≥18 years9th December 2020 to 1st September 20212.3 million doses (1 and 2)MHRA (Yellow Card Scheme) [
      • Medicines & Healthcare products Regulatory Agency
      ]
      CurevacNot authorized
      AZD1222Thromboembolic events0.61/millionIndia≥18 yearsDate not specifiedRetrospective survey of 75 random subjectsRajpurohit et al. [
      • Rajpurohit P.
      • Suva M.
      • Rajpurohit H.
      • Singh Y.
      • Boda P.
      A Retrospective observational survey of adverse events following immunization comparing tolerability of covishield and covaxin vaccines in the real world.
      ]
      Thrombosis with thrombocytopenia syndrome

      Capillary Leak Syndrome

      Myocarditis

      Pericarditis

      Anaphylaxis or anaphylactoid reactions
      14.9/million

      20.5/million

      12 cases among 48,9 million doses

      2.1/million

      3.3/million

      816 cases among 48.9 million doses
      UK≥18 years

      18–49

      ≥18 years
      9th December 2020 to 1st September 202148.9 million doses (1 and 2)MHRA (Yellow Card Scheme) [
      • Medicines & Healthcare products Regulatory Agency
      ]
      Guillain-Barré syndrome833 cases among 592 million dosesWorldwide≥18 yearsBy 25th July 2021592 million dosesEMA []
      Thrombosis with thrombocytopenia syndrome1503 cases among 592 million dosesWorldwide≥18 yearsBy 25th July 2021592 million dosesEMA []
      JanssenThrombosis with thrombocytopenia syndrome

      Guillain–Barré syndrome
      45 cases for 14.3 million doses (3/million)

      185 cases for 14.3 millions
      USA≥18 yearsAs of 1st September202114.3 million dosesUS CDC []
      Sputnik VExpected local and systemic reactions

      The most frequent symptoms were local pain, asthenia, headache, and joint pain
      2.1% participants suffered severe reactions in San Marino's populationRepublic of San Marino18–89 years4th March to 8th April 202Cohort of 2558 participantsMontalti et al. [
      • Montalti M.
      • Soldà G.
      • Di Valerio Z.
      • Salussolia A.
      • Lenzi J.
      • Forcellini M.
      • et al.
      ROCCA observational study: early results on safety of Sputnik V vaccine (Gam-COVID-Vac) in the Republic of San Marino using active surveillance.
      ]
      5% of serious adverse events (n = 34)Argentina18–80 years5th January to 20, 2021707 participantsPagotto et al. [
      • Pagotto V.
      • Ferloni A.
      • Mercedes Soriano M.
      • Díaz M.
      • Braguinsky Golde N.
      • González M.I.
      • et al.
      Active monitoring of early safety of Sputnik V vaccine in Buenos Aires, Argentina.
      ]
      NVX-CoV2373Not authorized
      EpiVacCoronaWe did not find any comparative studies addressing post-authorization safety
      ZF2001We did not find any comparative studies addressing post-authorization safety
      ConvideciaWe did not find any comparative studies addressing post-authorization safety
      CoronaVacBell's palsy

      Encephalopathy
      3.8/100 000

      0.01/100 000
      Hong Kong≥12 yearsUp to 31st Augustn = 2 811 500 dosesHongkong Drug Office [
      Hong Kong Drug Office
      Safety Monitoring of COVID-19 Vaccines in Hong Kong [Internet].
      ]
      Anaphylaxis

      Thromboembolic events

      Bell's palsy

      Guillain–Barré syndrome
      2/million

      1.15/million

      8.73/million

      0.29/million
      Chile≥16 years24th December 2020 to 14th May 2021n = 13 862 155 dosesInstituto de Salu Publica de Chile (ISP) [
      Instituto de Salud PublicaMinisterio de SaludGobierno de Chile
      Quinto Informe Estadistico: ESAVI asociados a la administracion de las vacunas SARS-CoV-2 en Chile [Internet].
      ]
      BBIBP-COrVNo serious side effects were reportedJordanMean age: 35–40 yearsNo date specifiedRetrospective survey of 409 participantsAbu-Hammad et al. [
      • Abu-Hammad O.
      • Alduraidi H.
      • Abu-Hammad S.
      • Alnazzawi A.
      • Babkair H.
      • Abu-Hammad A.
      • et al.
      Side effects reported by Jordanian Healthcare workers who received COVID-19 vaccines.
      ]
      No severe side effects were reported.Iraq≥18 yearsApril 2021Retrospective cross-sectional study of 1012 participantsAlmufty et al. [
      • Almufty H.B.
      • Mohammed S.A.
      • Abdullah A.M.
      • Merza M.A.
      Potential adverse effects of COVID19 vaccines among Iraqi population; a comparison between the three available vaccines in Iraq; a retrospective cross-sectional study.
      ]
      CovaxinIndian Ministry of Health and Family Welfare and a retrospective cohort reported no serious adverse effects associated to CovaxinIndia≥18 yearsNo date specified

      Retrospective survey of 75 random subjects
      Indian Ministry of Health and Family Welfare

      Rajpurohit et al. [
      • Rajpurohit P.
      • Suva M.
      • Rajpurohit H.
      • Singh Y.
      • Boda P.
      A Retrospective observational survey of adverse events following immunization comparing tolerability of covishield and covaxin vaccines in the real world.
      ]
      CIGB-66We did not find any comparative studies addressing post-authorization safety
      QaeVacWe did not find any comparative studies addressing post-authorization safety
      COVIran BarkatWe did not find any comparative studies addressing post-authorization safety
      Occurrence of adverse events changes with age. Myocarditis associated with mRNA vaccination was identified mainly among males aged <30 years with 39–47 cases per million vaccine doses in the USA (versus three to four myocarditis cases expected among male aged ≥30 years) [
      • Gargano J.W.
      Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the advisory committee on immunization practices — United States, June 2021.
      ]. On 23rd April, the EMA estimated two cases of thrombosis with thrombocytopenia (TTS) associated with AZD1222 per 100 000 doses for people aged 20–49 years, one case/100 000 doses for those aged 50–69 years, and even lower case rates (<1/100 000 doses) for older people. Similarly, the case rate of TTS was higher for the Janssen vaccine among young women. Surveillance studies found rare cases of Bell's palsy (3.8 cases per 100 000), anaphylaxis (two cases per million), thromboembolic event (1.2 cases per million), GBS (0.29 cases per million) associated with CoronaVac. Several observational and survey studies with low sample sizes did not find specific severe adverse events for Sputnik V, BBIBP-COrV, or Covaxin. Studies on adverse events were lacking for CIGB-66, QazVac, COVIran, Barkat, ZF2001, and EpiVacCorona. Pregnant women were excluded from clinical trials, but surveillance systems did not report an excess of adverse pregnancy and neonatal events after mRNA vaccination [
      • Shimabukuro T.T.
      • Kim S.Y.
      • Myers T.R.
      • Moro P.L.
      • Oduyebo T.
      • Panagiotakopoulos L.
      • et al.
      Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons.
      ,
      • Zauche L.H.
      • Wallace B.
      • Smoots A.N.
      • Olson C.K.
      • Oduyebo T.
      • Kim S.Y.
      • et al.
      Receipt of mRNA covid-19 vaccines and risk of spontaneous abortion.
      ], while an increased risk of severe COVID-19 in pregnancy and babies' admission in the neonatal unit was consistently observed [
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • Yap M.
      • Chatterjee S.
      • Kew T.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      ].

      Limitations of this review

      This review has several limitations. Several analyses were not peer-reviewed, and only press communications or regulatory market authorization files were available for CoronaVac, BBIBP-CorV, Wuhan inactivated vaccine, Covaxin and NVX-CoV2373. Clinical trials used different definitions for COVID-19 and different primary endpoints, which make direct comparisons difficult. Janssen's primary endpoint is moderate/severe/critical COVID-19 whereas Pfizer and Moderna included mild COVID-19. The endpoint time was also heterogeneous across trials, but most trials used 14 days after the full immunization.
      Observational studies, unlike randomized studies, cannot guarantee comparability in the exposition of different populations to SARS-CoV-2 and to the variants of concern. Indeed, real-world studies present large variations in time post-vaccination, exposition to SARS-CoV-2 strain, susceptibility to infection (previously infected or not), study population (healthcare workers, older adults, immunocompromised patients, those with chronical medical conditions, etc.). Moreover, due to a lack of randomization, observational studies are subject to bias when assessing effectiveness, such as misclassification from diagnostic errors, imbalances in socioeconomic status, exposure risk, healthcare-seeking behaviours, or immunity status between vaccinated and unvaccinated groups. Not all the observational studies used adjustments to take into account confounding biases. For example, healthcare workers treating COVID-19 patients may be more frequently exposed to SARS-CoV-2, leading to decreased estimates of effectiveness. Various designs—cohort, case–control study, test-negative design (TND)—were used in observational studies, each of them having limitations. Cohorts require large sample sizes for uncommon outcomes (i.e. severe COVID-19), but vaccination status may be more difficult to determine in retrospective cohorts. In case–control studies, vaccinated people may be more likely to seek health care and SARS-CoV-2 testing, biasing toward a reduction in the estimation of effectiveness.

      Conclusion

      To date, the availability of data varies greatly depending on the vaccine considered. mRNA vaccines, AZD1222, Ad26.COV2.S, Sputnik V, NVX-CoV2373, Ad5-nCoV, BBIBP-COrV, CoronaVac, COVAXIN and Wuhan inactivated vaccine showed an efficacy against COVID-19 in >50% in phase III studies. Most observational studies assessed the mRNA vaccines, CoronaVac and AZD1222 which appear to be safe and highly effective tools to prevent severe disease, hospitalization and death against all variants of concern (Alpha, Beta, Gamma and Delta). Large observational studies were lacking for several authorized vaccines: Sputnik V, Sputnik V Light, BBIBP-CorV, COVAXIN, EpiVacCorona, ZF2001, Abdala, QazCovid-In, Wuhan Sinopharm inactivated vaccine, KoviVac and COVIran Barekat. The protection against symptomatic and asymptomatic infection was high for Alpha, Beta and Gamma for mRNA vaccines and AZD1222. mRNA vaccines and Ad26.COV2.S were associated with a faster decline in viral load against several variants, including Delta, and a lower probability of viral culture positivity. Effectiveness against infection and COVID-19 declined following infection with the Delta variant and over time, possibly due to a waning of immunity.
      Heterologous prime-boost vaccination and a third dose of vaccine both induced a strong humoral response. Vaccinating previously infected people with a single dose provided an equivalent neutralizing response compared to people vaccinated with two doses against all the variants.
      According to safety monitoring, reported serious adverse events were very rare and the benefits of COVID-19 vaccination far outweighed the potential risks.
      More research is needed to consider booster doses, heterologous vaccination, dosing intervals, vaccine breakthrough infections, and duration of vaccine immunity against variants of concern.

      Author contributions

      TF and NPS designed and conducted the research. TF wrote the first draft of the paper. All authors (TF, YK, CJM, JG, NPS) contributed to the data interpretation, revised each draft for important intellectual content, and read and approved the final manuscript.

      Transparency declaration

      All authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. Thibault Fiolet received a PhD grant from the Fondation Pour la Recherche Médicale (FRM) n° ECO201906009060 . This funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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