Comparing COVID 19 Vaccines For Their Characteristics, Efficacy

Journal Pre-proof
Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness

against SARS-CoV-2 and variants of concern: A narrative review
Thibault Fiolet, Yousra Kherabi, Conor-James MacDonald, Jade Ghosn, Nathan

Peiffer-Smadja
PII: S1198-743X(21)00604-2
DOI: https://doi.org/10.1016/j.cmi.2021.10.005
Reference: CMI 2721
To appear in: Clinical Microbiology and Infection
Received Date: 3 August 2021

Revised Date: 7 October 2021
Accepted Date: 16 October 2021
Please cite this article as: Fiolet T, Kherabi Y, MacDonald C-J, Ghosn J, Peiffer-Smadja N, Comparing
COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and
variants of concern: A narrative review, Clinical Microbiology and Infection, https://doi.org/10.1016/
j.cmi.2021.10.005.
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© 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.
1 Title: Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against
2 SARS-CoV-2 and variants of concern: A narrative review
4 Authors: Thibault Fiolet1*, Yousra Kherabi2,3, Conor-James MacDonald1, Jade Ghosn2,3, Nathan
5 Peiffer-Smadja2,3,4
1
7 Paris-Saclay University, UVSQ, INSERM, Gustave Roussy, "Exposome and Heredity" team, CESP
8 UMR1018, Villejuif, France
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2
9 Université de Paris, IAME, INSERM, Paris, France
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11 3
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Infectious and Tropical Diseases Department, Bichat-Claude Bernard Hospital, AP-HP, Paris, France
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13 National Institute for Health Research Health Protection Research Unit in Healthcare Associated
14 Infections and Antimicrobial Resistance, Imperial College, London, UK

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16 *Corresponding author:
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17 Email: t.fiolet@outlook.fr
18
19
20
21 Abstract: 295 words
22 Manuscript: 3552 words
23
24
25
26
27
1
28 Abstract
29 Background
30 Vaccines are critical cost-effective tools to control the COVID-19 pandemic. However, the emergence
31 of SARS-CoV-2 variants may threaten the global impact of mass vaccination campaigns.
32 Objectives
33 The objective of this study was to provide an up-to-date comparative analysis of the characteristics,
34 adverse events, efficacy, effectiveness and impact of the variants of concern for nineteen COVID-19
35 vaccines.
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36 Sources
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37 References for this review were identified through searches of PubMed, Google Scholar, BioRxiv,
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38 MedRxiv, regulatory drug agencies and pharmaceutical companies’ websites up to September 22nd,
39 2021.
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40 Content
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41 Overall, all COVID-19 vaccines had a high efficacy against the original strain and the variants of
42 concern, and were well tolerated. BNT162b2, mRNA-1273 and Sputnik V had the highest efficacy
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43 (>90%) after two doses at preventing symptomatic cases in phase III trials.
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44 mRNA vaccines, AZD1222, CoronaVac were effective at preventing symptomatic COVID-19 and
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45 severe infections against Alpha, Beta, Gamma or Delta. Regarding observational real-life data, full
46 immunization with mRNA vaccines and AZD1222 seems to effectively prevent SARS-CoV-2
47 infection against the original strain, Alpha and Beta but with reduced effectiveness against the Delta
48 strain. A decline in infection protection was observed at 6 months for BNT162b2 and AZD1222.
49 Serious adverse event rates were rare for mRNA vaccines (anaphylaxis: 2.5-4.7 cases per million
50 doses), myocarditis (3.5 cases per million doses) and were similarly rare for all other vaccines. Prices
51 for the different vaccines varied from $2.15 to $29.75 per dose.
52 Implications
53 All vaccines appeared to be safe and effective tools to prevent severe COVID-19, hospitalization, and
54 death against all variants of concern, but the quality of evidence greatly varied depending on the
55 vaccines considered. There are remaining questions regarding booster dose and waning immunity, the
2
56 duration of immunity and heterologous vaccination. COVID-19 vaccine benefits outweigh risks,
57 despite rare serious adverse effect.
58
59
60 Background
61
62 The implementation of SARS-CoV-2 vaccines is a major asset to slow down the COVID-19
63 pandemic. At the time of writing, more than 100 vaccines have been developed, and 26 vaccines have
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64 been evaluated in phase III clinical trials, according to the World Health Organization (WHO) (1).
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65 Recently, several variants of concern (VOC) have emerged such as Alpha (known as 501Y.V1 with
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66 GISAID nomenclature or B.1.1.7 variant with PANGO nomenclature), Beta (501Y.V2 or B.1.351),
67
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Gamma (501Y.V3 or P1) and Delta (G/478K.V1 or B.1.617.2). These variants have been associated
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68 with an increase in the transmission or the mortality of COVID-19 (2–6) or may escape immunity
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69 when compared to the original strain or D614G variant (7–11).
70
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71 While phase III trials assess the efficacy in controlled conditions, phase IV studies evaluate the real
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72 world effectiveness of the vaccines in an observational design, among a larger general population.
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73 These studies bring crucial information about rare or long-term effects, the prevention of
74 asymptomatic infection and the severity of COVID-19.
75
76 The administration of COVID-19 vaccines is a major priority for many countries around the world.
77 Due to the speed of production of scientific data in this pandemic context, it can be difficult for
78 healthcare professionals to update themselves on the latest data concerning COVID-19 vaccines.
79
80 The objective of this review is to provide an up-to-date comparative analysis of the characteristics,
81 adverse events, efficacy, effectiveness and impact of the variants of concern on the following nineteen
82 COVID-19 vaccines: mRNA vaccines: BNT16b2, mRNA-1273, CVnCoV ; viral vector vaccines:
83 AZD1222, Sputnik V, Sputnik V Light, Ad5-nCoV (Convidecia), Ad26.COV2.S ; inactivated
3
84 vaccines: NVX-COV2373, CoronaVac, BBIBP-CorV, Wuhan Sinopharm inactivated vaccine,
85 Covaxin, QazVac, KoviVac, COVIran Barekat ; protein-based vaccine: EpiVacCorona, ZF2001,
86 Abdala.
87
88 Methods
89 Electronic searches for studies were conducted on Pubmed, Google scholar until September 22nd, 2021
90 using the search terms “SARS-CoV-2”, “COVID-19”, “efficacy”, “effectiveness”, “neutralization
91 assays”, “neutralization antibodies” in addition to the scientific or commercial name of the vaccines
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92 reported by WHO in phase III/IV. The ClinicalTrials.gov database was consulted using the terms
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93 “COVID-19” and “vaccine”. BioRxiv and MedRxiv, regulatory drug agencies and pharmaceutical
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94 companies’ websites were also consulted for unpublished results and additional information. Vaccines
95
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included in this review were approved in at least one country. CVnCoV and NVX-CoV2373 were in
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96 rolling review by the European Medicine Agency (EMA) and were included in this review.
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97
98 Efficacy refers to the degree to which a vaccine prevents symptomatic or asymptomatic infection
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99 under controlled circumstances such as clinical trials. Effectiveness refers to how well the vaccine
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100 performs in the real world. In clinical trials, the main endpoint was the prevention of symptomatic
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101 COVID-19 whereas in observational studies, endpoints were various: asymptomatic SARS-CoV-2
102 infection, COVID-19, hospitalization or mortality.
103
104 Regarding seroneutralization assays, we extracted the age of the study population, dosage, and fold
105 decrease in geometric mean titer for 50% neutralization compared to the SARS-CoV-2 reference strain
106 for each vaccine and each SARS-CoV-2 variant when it was available.
107
108 Evidence on vaccine efficacy and effectiveness
109 At the time of this review, seventeen vaccines have been authorized in at least one country
110 (Supplementary Table S1) and two vaccines (CVnCoV and NVX-CoV2373) are under evaluation.
111
4
112 We briefly compared the COVID-19 vaccines schedule, type of vaccine, manufacturer, dosage,
113 conditions of use/storage/transport, composition and price (Table 1). The main results of phase III
114 clinical trials for each vaccine are described in Table 2 and in Figure 1). Characteristics of SARS-
115 CoV-2 variants (Alpha, Beta, Gamma, Epsilon, Eta, Zeta, Iota, Kappa and Delta) are described in
116 Table 3. The results of observational real-world studies are specified in Figures 2, 3, 4 and in
117 Supplementary Table S2. Seroneutralization assays results are summarized in Figure 5 using
118 boxplots per vaccine and per variant and Supplementary Table S3 describes the 54 studies in detail.
119
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5
120 Table 1: Characteristics of COVID-19 vaccines
121 NA, not available information
122 EU, European Union
123
Injection
Manufacture Type of Dose interval Cost for one
Vaccine Dose Condition of use/Storage Composition
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trial
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6
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.
A synthetic messenger
Frozen vials prior to use can be
ribonucleic acid (mRNA)
stored before dilution: -80°C to
encoding the Spike protein of
-60°C up to the end of its expiry
SARS-CoV-2, lipids ((4-
date or at -25°C to -15°C for up
f
hydroxybutyl)azanediyl)bis(hexa EU and USA:
to two weeks
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30 µg ne-6,1-diyl)bis(2- $19.50
hexyldecanoate), 2-
Pfizer/BioNte Intramuscularly Vials prior to dilution may be
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BNT16b2 RNA-based 5-7-dose vial [(polyethylene glycol)-2000]- African Union:
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ch 2 doses 21 days stored at +2°C to +8°C for up to
0.3mL per dose N,N-ditetradecylacetamide, 1,2- $6.75
apart 31 days or may be at room
distearoyl-sn-glycero-3-
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temperature up to +25°C for no
phosphocholine, and cholesterol), Brazil: $10
more than 2 hours prior to use,
potassium chloride, monobasic Colombia: $12
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or can be thawed in the
potassium phosphate, sodium
refrigerator for 2-3 hours or at
chloride, dibasic sodium
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room
phosphate dihydrate, and sucrose
temperature (up to +25°C) for
30 minutes.
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After dilution: +2°C to +25°C
Have to be used within 6 hours
from the time of dilution
7
A synthetic messenger
ribonucleic acid (mRNA)
encoding the Spike protein of
Supplied as a frozen suspension
SARS-CoV-2. The vaccine also
stored between -50°C to -15°C
contains the following
EU: $25.5
100 µg ingredients: lipids (SM-102, 1,2-
Unopened vial: +2°C to +8°C USA: $15
dimyristoyl-rac-glycero-3-
mRNA- Intramuscularly for up to 30 days Argentina:
Moderna RNA-based 11 or 15-dose vial methoxypolyethylene glycol-
1273 2 doses 28 days +8°C to +25°C for up to 24 $21.5
0.5mL per dose 2000 [PEG2000-DMG],
apart hours Botswana:
cholesterol, and 1,2-distearoyl-sn-
$28.8
glycero-3-phosphocholine
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After opening: +2°C to +25°C
[DSPC]), tromethamine,
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and discarded after 12 hours
tromethamine hydrochloride,
acetic acid, sodium acetate, and
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sucrose
Concentrated CVnCoV will be
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stored frozen at -60°C (in
Intramuscularly clinical trial)
12 µg
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CVnCoV CureVac RNA-based 2 doses 28 days CVnCoV must be diluted NA NA
apart Unopened vial: 3 months at
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+2°C to +8°C
Room temperature for 24 hours
Chimpanzee Adenovirus
ur encoding the SARS-CoV-2 Spike

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glycoprotein (ChAdOx1-S)*, not
Do not freeze
less than 2.5 × 108 infectious
10
5x10 viral units (Inf.U)*Produced in
Unopened vial: 6 months (+2°C
particles genetically modified human
AZD1222 to +8°C)
(standard dose) embryonic kidney (HEK) 293
AstraZeneca/ Non- $2.15 in the EU
Intramuscularly cells and by recombinant DNA
ChAdOx1 University of replicating After opening: no more than 48
8 doses or 10 2 doses 4-12 technology
nCoV-19 Oxford viral vector hours in a refrigerator (+2°C to $4-6 elsewhere
doses of 0.5 ml weeks apart L-Histidine L-Histidine
vaccine +8°C)
per vial hydrochloride monohydrate
Used at temperature up to
Magnesium chloride hexahydrate
+30°C for a single period of up
Polysorbate 80 (E 433) Ethanol
to 6 hours
Sucrose Sodium chloride
Disodium edetate (dihydrate)
Water for injection
8
replication-incompetent
recombinant adenovirus type 26
Should be protected from light
vector expressing the severe acute
Supplied as a liquid suspension
respiratory syndrome
Unopened vial can be stored at
coronavirus-2 spike protein in a
+2°C to +8°C until the
5x1010 viral stabilized conformation.
expiration date or at +9°C to EU: $8.5
Non- particles Intramuscularly (5×1010 vp)
Ad26.COV2 Johnson & +25°C for up to 12 hours USA: $10
replicating
.S Johnson African Union:
viral vector 10 dose of 0.5mL A single dose citric acid monohydrate,
After the first dose has been $10
per vial trisodium citrate dihydrate,
withdraw: the vial is held
ethanol, 2-hydroxypropyl-β-
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between +2°C and +8°C for up
cyclodextrin (HBCD),
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to 6 hours or at room
polysorbate 80, sodium chloride,
temperature for up to 2 hours
sodium hydroxide, and
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hydrochloric acid
Two vector components, rAd26-S
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and rAd5-S
1011 viral
Tris (hydroxymethyl)
particles per dose
lP
Gam- Intramuscularly Transport: two forms: aminomethane, sodium chloride,
Gamaleya Non- for each
COVID- lyophilized or frozen sucrose, magnesium chloride
Research replicating recombinant <$10
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Vax 2 doses 21 days hexahydrate,
Institute viral vector adenovirus
Sputnik V apart Storage: +2°C to +8°C ethylenediaminetetraacetic acid
(EDTA) disodium salt dihydrate,
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0.5 mL/dose
polysorbate-80, ethanol 95%, and
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water for injection
Intramuscularly
5 µg protein and Shipped in a ready-to-use liquid SARS-CoV-2 rS with Matrix-M1 $20.9 for
NVX- Protein-
Novavax 50 µg Matrix-M formulation adjuvant (5 μg antigen and 50 μg Denmark
CoV2373 based 2 doses 21 days
adjuvant Storage: +2°C to +8°C adjuvant) COVAX: $3
apart
Intramuscularly
EpiVacCoro Protein- 225 µg protein Storage between +2°C and
VECTOR 2 doses 21 days NA NA
na based 0.5mL/dose +8°C
apart
9
Institute of
Microbiology,
Chinese
Academy of
Protein- 25 µg protein Storage between +2°C and
ZF2001 Sciences, and Intramuscular NA NA
based 0.5mL/dose +8°C
Anhui Zhifei
Longcom
Biopharmaceu
tical.
the Recombinant Novel
Coronavirus Vaccine
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(Adenovirus Type 5 Vector)
Supplied as a vial of 0.5mL
Convidecia Non- 1010 viral Intramuscularly Mannitol, sucrose, sodium
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Storage between +2°C and Pakistan private
™
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CanSino replicating particles per 0·5 chloride, magnesium chloride,
+8°C market: $27.2
Ad5-nCoV viral vector mL in a vial. Single dose polysorbate 80, glycerin, N- (2-
Do not freeze
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hydroxyethyl), piperazine-N- (2-
ethanesulfonic acid) (HEPES),
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sterile water for injection as
solvent
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Supplied as a vial or syringe of Inactivated CN02 strain of
China: $29.75
0.5mL SARS-CoV-2 created with Vero
Intramuscularly Do not freeze cells
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3 µg Ukraine: $18
Sinovac Inactivated Protected from light Aluminum hydroxide, disodium
CoronaVac Philippines:$14.
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Biotech virus 2 doses 28 days Storage and transport between hydrogen phosphate
0.5mL per dose 5
apart +2°C and +8°C dodecahydrate, sodium
Brazil: $10.3
Shake well before use dihydrogen phosphate
Cambodia: $10
Shelf-life: 12 months monohydrate, sodium chloride
Inactivated virus
Supplied as Pre-filled syringe or Argentina,
Sinopharm/ 19nCoV-CDC-Tan-HB02
Intramuscularly vial Mongolia: $15
Beijing 4 µg
BBIBP- Inactivated Cannot be frozen Senegal: $18.6
Institute of Excipients: disodium hydrogen
COrV virus 2 doses 21 to 28 Protected from light China: $30
Biological 0.5mL per dose phosphate, sodium chloride,
days apart Store and transport refrigerated Hungary: $36
Products sodium dihydrogen phosphate,
(+2°C to +8°C)
aluminum hydroxide adjuvant
10
Sinopharm/Ch
inese Inactivated
Wuhan NA NA NA NA NA
Academy of virus
Science
6μg of whole-virion inactivated
SARS-CoV-2 antigen (Strain:
6μg NIV-2020-770), and other
Intramuscularly Supplied as a single dose or inactive ingredients such as
India: $3-5
Bharat Inactivated Single dose: multidose vial aluminum hydroxide gel (250
Covaxin Brazil: $15
Biotech virus 0.5mL 2 doses 28 days Do not freeze μg), TLR 7/8 agonist
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Botswana: $16
10-dose or 20- apart Stored at +2°C to +8°C (imidazoquinolinone) 15 μg, 2-
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dose vial phenoxyethanol 2.5 mg, and
phosphate ®buffer saline up to
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0.5 m
Recombinant protein of the
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SARS-CoV-2 virus receptor-
Center for
0.05mg binding domain (RBD) 0.05 mg
Genetic
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recombinant Intramuscularly Supplied as a multidose vial Thiomersal 0.025 mg
CIGB-66 Engineering Protein-
protein 3 doses at 0, 14, Do not freeze Aluminum hydroxide gel (Al³ +) NA
Abdala and based
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28 days Stored at +2°C to +8°C Disodium hydrogen phosphate
Biotechnology
0.5mL per dose Sodium dihydrogen phosphate
(CIGB)
dihydrate
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Kazakh
Research
QazVac Intramuscularly
Institute for Inactivated
QazCovid- - 2 doses 21 days Stored at +2°C to +8°C NA NA
Biological virus
In apart
Safety
Problems
Inactivated viral particles and a
Shifa Pharmed 5μg inactivated Intramuscularly
Coviran Inactivated mixture
Industrial purified virus 2 doses 28 days Stored at +2°C to +8°C NA
Barkat virus 2% adjuvant® Alhydrogel
Group 0.5 mL per dose apart
(aluminium hydroxide)
11
Chumakov Inactivated
KoviVac NA NA NA NA NA
Center virus
124
125 *Prices were retrieved from

126 https://www.unicef.org/supply/covid-19-vaccine-market-dashboard
127 https://www.theguardian.com/world/2021/aug/11/covid-19-vaccines-the-contracts-prices-and-profits
128
f
Composition and conditions of use references are in the supplementary Table S1
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12
129 Randomized clinical trials on vaccine efficacy
130 In Phase III trials (Table 2 and Figure 1), all the main outcomes were efficacy against symptomatic
131 infection after the second dose. In most trials, the strain was not sequenced.
132 Messenger RNA (mRNA) Vaccines
133 mRNA-based drugs are new but not unknown. In 1990, the direct injection of mRNA in mouse muscle
134 cells proved the feasibility of mRNA vaccines(12). mRNA instability, high innate immunogenicity
135 and delivery issues were the main obstacles. BNT162b2 and mRNA-1273 vaccines against SARS-
136 CoV-2 were the first authorized mRNA-based vaccines. They contain the mRNA of the antigen of
f
137 interest which enters cells and is translated into the spike protein to induce an immune response.
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138 Against the historical strain, BNT162b2 and mRNA-1273 vaccines had an efficacy of >90% at 5-6
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139 -p
months follow-up post second dose whereas CVnCoV had a lower efficacy of 48%.
140
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141 Viral vector vaccines
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142 Viral vectors are delivery systems containing nucleic acid encoding an antigen. AZD1222, Ad5-nCoV
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143 and Sputnik V had an efficacy of 65%-91.6% against the historical strain. AZD1222 had an efficacy of
144 70.4 against Alpha. Ad26.COV2.S had an efficacy of 69.4% in Brazil (mainly P2). AZD1222 and
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145 Ad26.COV2.S had an efficacy of 10.4% and 64.7%, respectively, against Beta in South Africa.
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146
147 Inactivated and protein subunit vaccines
148 Inactivated vaccines are whole viruses that cannot infect cells and replicate (13). Subunit vaccines are
149 made of fragments of proteins or polysaccharides. NVX-COV2373 had an efficacy of 89-91.6%
150 against the historical strain and 86.3-93.2% against Alpha and 60% against Beta. CoronaVac, BBIBP-
151 CorV, Wuhan inactivated vaccine, Covaxin and Abdala had an efficacy of 50.6-92.3% and the SARS-
152 COV-2 strains were not specified. KoviVac, Barekatn QazVac, RBD-Dimer, EpiVacCorona had not
153 phase III trial data published at the time of this review.
154
155
156
157
13
158 Table 2: Phase III Trials for COVID-19 vaccines
159 NA, not available information
160 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,
161 EpiVacCorona, ZF2001 and Sputnik V Light
Vaccin Any unsolicited

Study Cut-off Hospitaliza
e Author Main endpoint Symptomatic COVID-19 Severe COVID-19 Serious adverse
population date tion
event
Cases
f
Cases among Efficacy
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Efficacy (%, among Place
Vaccine Placebo Vaccine (%, Vaccine
95%CI) Placebo bo
group 95%CI)
group
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88.9%
82% (20.1 to
July 27, After dose 1 50/21,314 275/21,258 0 4 NA 0.6% 0.5%
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(75.6 to 86.9) 99.7)
Polack 2020 -
et al. USA, November
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After dose 2
(14) Argentina, 14, 2020
Covid-19 with onset
Brazil, Median 75%
at least 7 days after 95%
BNT162b2 (RNA-based)
follow-up: 2 0.5%
na
Germany, S. 8/18,198 162/18,325 1 4 (-152.6%- NA 0.6%
the second dose (90.3 to 97.6)
Africa, month 99.5%)
without prior
Turkey
ur
infection
July 27, After dose 2
16 years
Jo
2020 - Covid-19 with onset
Thomas
March 13, at least 7 days after 91.3% 95.7% (73.9
et al.
2021 the second dose
77/20,998 850/20,713
(89.0 to 93.2)
1 23
to 99.9)
NA 1.2% 0.7%
(15)
6 months without prior
follow-up infection
October 15, After dose 2
No cases of
2020 - Covid-19 with onset
Frenck severe
USA January 12, at least 7 days after 100% (75.3 to
et al.
12-15 years 2021 the second dose
0/1,005 16/978
100)
0 0 Covid-19 NA 0.4% 0.1%
(16) were
2 months without prior
observed
follow-up infection
(RNA-based)
80.2% NA NA NA NA NA
mRNA-1273
July 27,
After dose 1 7/996 39/1079 NA
2020 - (55.2 to 92.5)
Baden et USA
November After dose 2 100% 3 in the
al. (17) ≥ 18 years 94.1%
21,2020 Covid-19 with onset 11/14,134 185/14,075
(89.3 to 96.8)
0 30 (no CI placebo 0.6% 0.6%
Median at least 14 days after estimated) group and 1
14
follow-up of the second dose in the
64 days without prior vaccine
infection group
March 26th,
Covid-19 with onset
2021
El Sahly at least 14 days after
USA Median 93.2% (91 to
et al. the second dose 55/14,287 744/14,164 2 106 98.2% NA 0.7% 0.6%
≥ 18 years follow-up of 94.8)
(18) without prior
5.3 months
infection
post dose 2
Argentina, 0
CVnCoV (RNA-based)
Belgium, hospitalizati
Colombia, on among
CureVa 40,000 adults
f
Dominican Estimated 77% against the vaccine
oo
c press 83 cases among the vaccine
Republic, completion COVID-19 of any moderate group On On
commun group 48% 9 36
Germany, date: May severity and severe 6 going going
ication 145 cases among the
r
Mexico, 15, 2022 disease hospitalizati
-p
(19) placebo group
Netherlands, ons among
Panama, the placebo
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Peru, Spain group
October 1, Alpha: 70.4% NA NA NA NA NA
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Symptomatic
2020 - (43.6 to 84.5)
Covid-19 with onset There were
Emary January 14,
at least 14 days after no cases of
na
et al. UK 2021 59/4,244 210/4,290 Non-VOC
the second dose hospitalizati
(20) Median lineages:
without prior on or death
AZD1222 (Non-replicating viral vector)
follow-up: 81.5% (67.9

infection
ur
not provided to 89.4)
ChAdOx1 nCoV-19 vaccine
April 23, 2
Jo
2020 - hospitalizati
Efficacy
December Symptomatic ons among
against
UK/Brazil/S 7, 2020 Covid-19 with onset the vaccine
Voysey 66,7% hospitalizati
outh Africa Median at least 14 days after group
et al.
follow-up the second dose
84/8,597 248/8,581 (57,4% to 0 15 on from 22
22
0.7% 0.8%
(21) 74%) days after
≥ 18 years post dose 2: without prior hospitalizati
vaccination:
53-90 days infection on among
100%
according to the placebo
the dose gap group
June 24, Mild-to-moderate
2020 to Covid-19 with onset
South No 13
Madhi November at least 14 days after 21.9 Zero
Africa 19/750 23/717 0 0 participant 14
et al. 9, 2020 the second dose (-49.9 to 59.8)
had severe
hospitalizati
events
event
(22) Median without prior on s
≥ 18 years COVID-19
follow-up infection
post dose 2: Against Beta variant 19/750 20/714 10.4% 0 0
15
156-121 at least 14 days after (-76.4 to 54.8)
days the second dose
(vaccinated without prior
– placebo) infection
Zero
hospitalizati
on among
Press
Preventing the vaccine
commun USA March 25, 141 symptomatic cases 76% (68 to
ication ≥ 18 years 2021
symptomatic
among 32,449 participants 82)
NA NA 100% group NA NA
COVID-19 Not
(23)
f
specified for
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the placebo
group
r
All: 66.9%
-p
(59.1 to 73.4)
Brazil, 2
re
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Prevent confirmed,
Argentina, (65 to 81.6) ons among
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severe/critical All: 76.7%
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Mexico, US, 52% (30.3 to 29
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14 days after 89.1)
South 67.4) hospitalizati
vaccination without
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EMA D614G All: 66.1%
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2 months 0
US
hospitalizati
Prevent confirmed, USA: 72%
ons among
Beta (94.5% moderate to (58.2 to 81.7)
the vaccine
in South severe/critical All: 85.4%
group
Africa) COVID-19 at least 66/19,306 193/19,178 South Africa: 5 34 (54.2 to
16
28 days after 64% (41.2 to 96.9
hospitalizati
Variant P2 vaccination without 78.7)
on among
(69.4% in prior infection
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group
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0 20
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NA
post dose 1: second dose
or severe
48 days
South August 17,
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(6.1 to 72.8%)
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25, 2020 COVID-19 at least
et
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44/1,357 29/1,327 HIV-negative NA NA NA NA 0.4% 0.2%
al.(27) participants:
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of cases in follow-up dose without prior
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South post dose 2: infection
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≥ 18 years 7 days after the 2nd 10 cases 96 cases 86.3% 0 1 - 0.5% 0.5%
al.(28) post dose 2: in placebo
dose without prior (95%CI: 71.3
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infection to 93.5)
against Alpha
January 25, 90.4% (82.9 o
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April 30,
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29) dose without prior
Follow-up: variants
infection
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Pakistan, COVID-19 disease

Convidecia™
viral vector)
CanSino 8 February, 68.83% NA NA 95.47% NA NA NA

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Mexico, 14 days after single

Biologic 2021
Russia, dose
s Inc Follow-up:
Chile and Symptomatic NA NA
docume not
Argentina COVID-19 disease
nt (30)
≥ 18 years
available
28 days after single
65.28% NA NA 90.07% NA NA NA
dose
17
Brazil all:
Brazil, December
Symptomatic 50,65%
Sinovac Turkey, 16,2020 Brazil: 253 cases/12,396
CoronaVac (Inactivated virus)
COVID-19 at least Turkey: Brazil:
docume Indonesia Follow-up: health workers NA NA NA NA NA
14 days after two 83.5% 100%
nt(31) ≥ 18 years not Turkey: 29 cases/1,322
doses Indonesia:
available
65%
1
September
hospitalizati
15, 2020 to
on in the
January 6,
Symptomatic placebo
Tanriov Turkey 2021
COVID-19 at least 83.5% (65.4 group
er et ≥ 18 years Median 9/6,559 32/3,470 NA NA NA 0.1% 0.1%
14 days after two to 92.1) 0
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on in the
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group
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2020 to
(inactivated virus)
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China, 20, 2020
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Al COVID-19, 14 days
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Kaabi et
and the follow-up
after the second 21/12,726 95/12,737
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na
infection at baseline
≥ 18 years after the 2nd
dose): 77
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days
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Wuhan inactivated
2020 to
Bahrain, December
Symptomatic
China, 20, 2020
vaccine
Al COVID-19, 14 days
Pakistan, Median 72.8% (58.1
Kaabi et
and the follow-up
after the second 26/12,743 95/12,737
to 82.4)
0 2 100% (NA) NA 0.5% 0.6%
al.(33) dose without prior
UAE (14 days
≥ 18 years after the 2nd
dose): 77
days
Symptomatic
(inactivate
COVAXI
Median
d virus)
Bharat COVID-19, 14 days

India follow-up: 127 symptomatic cases 78% (61 to 100% (60 to
N
Biotech( after the second NA NA NA NA NA

≥ 18 years not among 25,800 participants 88) 100)
34) dose without prior
available
18
(Protein- Median
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based) release Cuba
follow-up: COVID-19 (not
NA NA 92.3% NA - NA NA NA -
not specified)
(35) available
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na
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19
162 Real world studies
163 Post-marketing surveillance studies results are summarized in Table 3 and detailed in Supplementary
164 Table 2. Most studies have a follow-up of 90 days post-vaccination.
165
166 Effectiveness against COVID-19 (symptomatic infection)
167 After full immunization, mRNA vaccines effectiveness against disease was 88-100% against Alpha
168 (36–43), 76-100% against Beta/Gamma (37,38,40), 47.3-88% against Delta (38,44–47), and 89-100%
169 when SRAS-CoV-2 strain was not sequenced(40,41,48–53) (Figure 2). AZD1222 effectiveness
f
170 against disease was 74.5% against Alpha (45) and 67% against Delta (44,54) in the UK. CoronaVac
oo
171 effectiveness was 65.9-73.8% against Alpha/Gamma/D614G strain in Chile and Brazil (55,56).
r
172 CoronaVac or BBIBP-COrV administration was associated with an effectiveness of 59% in China(57).
173
-p
re
174 Effectiveness against COVID-19 related hospitalization and death
lP
175 After full immunization (Figure 3), mRNA vaccine or AZD1222 effectiveness against hospitalization
na
176 or death was over 87-94% (48,58) when the strain was not sequenced, 89-95% against Alpha
177
ur
(36,38,39), 95% against Beta/Gamma (38), 96% against Alpha/Delta (39), 80-95% against Delta
178 (59,60). CoronaVac had a strong effectiveness against hospitalization (87.5%) and mortality (86.3%)
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179 after full immunization(56). Ad26.COV1.S had an effectiveness of 60-85% against Delta (60,61).
180 Overall, mRNA-vaccine and CoronaVac effectiveness was reduced for Delta infection but they still
181 offered a high level of protection against severe COVID-19 and hospitalization for all variants after
182 full immunization (36,38,39,43,48,56,59,62,63).
183 Effectiveness against asymptomatic SARS-CoV-2 infection
184 After full immunization, effectiveness was 90-92% for AZD1222 or BNT162b2 against unspecified
185 strains (64,65) (Figure 4). For mRNA vaccines, effectiveness against infection was 89.5-99.2%
186 against Alpha(36,37,48,49,49,66), 75-96.4% against Beta (37,49), 42-84.4% against Delta (44,66–69)
187 and 80-98.2% against unspecified strains (48,50,51,62,70–78). AZD1222 had an effectiveness of 49-
20
188 67% in the UK (44,66,79). mRNA vaccines and Ad26.COV2.S vaccines in the USA had an
189 effectiveness of 47-80% against Delta (59,80,81). Among pregnant women, a single dose or two doses
190 led to an effectiveness of 78% against the original strain and 96% against Alpha, respectively. These
191 previous studies focused on 6 years people but a retrospective cohort of 12-15 years teenagers in
192 Israel also reported a high effectiveness of 91.5% against Delta infections (82).
193
194 Impact on viral load, infectivity, transmission and long COVID
195 Before Delta propagation, mRNA vaccines were associated with a lower viral load and a reduced
f
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196 duration of illness (83,84). Against Delta, surveillance studies in the US found both vaccinated and
197 unvaccinated people had similarly low Cycle threshold (Ct) values indicating high viral load (85,86).
r
198 -p
However, the large UK REACT-1 study using random sampling and including participants who tested
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199 positive without showing symptoms study showed vaccinated people had a lower viral load on average
200
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(79). A preprint in Singapore found BNT162b2 vaccination was associated with a faster decline in
201 viral loads among vaccinated people (87). Ad26.COV2.S and BNT162b2 vaccines were associated
na
202 with a lower probability of viral culture positivity suggesting less infectious Delta virus shedding for
ur
203 vaccinated people (88). Before Delta spreading, a study in England reported a reduced transmission
204 associated with BNT162b2 or AZD1222 vaccines in a household setting(89) and two other
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205 preliminary analyses confirmed these results(90,91). A Chinese preprint analyzed infections among
206 5,153 participants with 73 close contacts COVID-19 cases and observed a higher infection risk among
207 unvaccinated or partially vaccinated participants (vs 2 doses of inactivated vaccines) (92). In a large
208 nested-case control study from the UK, participants with one or two vaccine doses reported to have
209 fewer symptoms and lower odds of having long COVID (symptoms over 28 days, OR = XXX after
210 two doses) (93).
211
212
213 Waning immunity
214 Several studies suggested that the levels of antibodies after BNT162b2, mRNA-1273 and
215 Ad26.COV2.S vaccines could last for at least six months but decreased over time afterward (94–97).
21
216 For mRNA-1273, at 6 months, neutralizing activity was maintained against Alpha, Gamma, Delta,
217 Epsilon whereas neutralizing activity considerably decreased against Beta for half the participants
218 (97).
219 Observational studies stratified by time since vaccination identified a decreasing effectiveness at 4-6
220 months (42-57%) for mRNA vaccines and 47.3% for AZD1222 against Delta infection (54,68,69,81).
221 In the USA, effectiveness of mRNA vaccines against symptomatic infection reduced from 94.3% in
222 June to 65,5% in July 2021. The effectiveness against hospitalization remained high (>85%) for
223 mRNA-1273 (92%), BNT162b2 (77-93%) and AZD-1222 (70.3%) at 4-6 months after full vaccination
f
224 (54,69,81,98) and 68% at >28 days after full immunization for Ad26.COV2.S (98). It is difficult to
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225 know if the reduction in effectiveness against Delta infection is due to waning immunity over time
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226 or/and variants escaping immunity and/or increasing in collective immunity.
227
-p
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228 Neutralization assays with variants of concern and variants of interest
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229 Mutations and variations occur in the SARS-CoV-2 virus due to evolution and adaptation processes
na
230 (99). Some SARS-CoV-2 variants of concern with mutations in the spike protein lead to an increased
231 transmissibility (100–105), which may be explained by an enhanced spike protein binding affinity for
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232 the ACE2 receptor. For example, Alpha and Beta have been shown to have a 1.98-times and 4.62-
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233 times greater binding affinity than original strain (106). These variants may cause more severe disease
234 (4) and/or have a potential ability to escape the host or vaccine-inducted immune response (7,10).
235 Results from several seroneutralization assays assessing the neutralizing response of vaccine-induced
236 antibodies are described in Figure 5 and in Supplementary Table 3. In general, Alpha had a minimal
237 impact on neutralization activity of antibodies by post-vaccination sera (Table 3). Neutralization was
238 further reduced for variants with mutation E484K, and Gamma. Beta had the highest reduction in
239 neutralizing titers. Data were lacking for C.1.2 identified in South Africa in May, 2021 but C.1.2 had a
240 1.7-fold higher substation rate than the current global substitution rate (107).
241
242
22
243
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23
244 Table 3: COVID-19 vaccines and variants
245 NA: Not available
SARS-CoV-2 B.1.1.7 B.1.351 B.1.1.28.1 .P1 B.1.617.2 B.1.617.1
variants 501Y.V1 501Y.V2 501Y.V3 (and AY sublineages)
WHO nomenclature Alpha Beta Gamma Delta Kappa
69/70del, 144del, N501Y, D80A, D215G, 241/243del, L18F, T20N, P26S, T19R, T95I, G142D, E156-, G142D, E154K,
A570D, D614G, P681H, K417N, E484K, N501Y, D614G, D138Y, R190S, K417T, F157-, R158G, , L452R, T478K, L452R, E484Q,
Key spike mutations T716I, S982A, D1118H A701V E484K, N501Y, D614G D614G, P681R, D950N ± (V70F, D614G, P681R,
H655Y, T1027I, A222V, W258L, K417N) Q1071H ± (T95I)
V1176F
UK South Africa Brazil and Japan India India
f
First detection
oo
September 2020 September 2020 December 2020 December 2020 December 2020
+56% in the UK (2) +50% in South Africa (108) +160% in Brazil (3,6) +40 to 60% in the UK (compared
r
Transmission +56-74% in Denmark,
-p
to Alpha)
compared to non- Switzerland, US (102) NA
+97% higher reproductive
VOC/VOI 43-100% higher
re
number (104)
reproductive number (104)
Increased 61-64%mortality May cause more severe cases
lP
Risk of mortality NA NA NA
in the UK (4) than Alpha (109)
No/Minimal Minimal to substantial Minimal to moderate 3-3.9 fold reduction for mRNA-
na
1273 (136–138)
0 to 3.3-fold reduction for No reduction for BBIBP-CorV 1.2 to 7.6 fold reduction
ur
BNT162b2 (9,110–122), (124,129) for BNT162b2 1.4 to 11.1 fold reduction for 2.6 to 7.5 fold
mRNA-1273 (8,9,115,123) BN162b2 (133,136,137,139–141) reudction for
Jo
1.3 to 38.45 fold reduction for 3.2 to 4.5 fold reduction BNT162b2
No reduction for Sputnik V, BNT162b2 (7,9,110– for mRNA-1273 3.1 to 9 for (133,136,139,146)
Impact on post-
vaccination sera Covaxin, , BBIBP-CorV 113,115,116,119,120,130) (110,112,115) AZD1222(133,140,142)
(118,124,125) 3.4 to 7 fold
(reduction in
9 fold reduction for 1.6 to 5.4 fold reduction for reduction for
neutralization 3.3 to 23.45 fold reduction for
AZD1222 (120) Ad26.COV2.S(134,137) mRNA-1273
activity compared to 1.5 to 4.1-fold reduction mRNA-1273 (9,115,123,131,132),
(138)
the original SARS- for CoronaVac AZD1222 (133)
CoV-2 or D614G) (124,126,127) 7.5 fold reduction for 2.5-fold for CoronaVac(143)
CoronaVac (126,127) 1 to 2.6 fold
3.3 to 5.3 fold reduction
3-fold for ZF2001(143) reduction for
2.1 fold reduction for CoronaVac (124,126)
3.4 fold reduction for AZD1222
AZD1222 (117) and NVX- (133,139,145)
CoV2373 (128) 6.1 fold reduction for Sputnik V Ad26.COV2.S (134) 2.5-fold for Sputnik V(144)
(118)
2.8 fold reduction for 4.6-fold for Covaxin(145).
24
14.5 fold reduction for NVX- Sputnik V (135)
CoV2373(132)
BNT162b2: BNT162b2: 75% (37) NA BNT162b2: 42-79% (44,66–69)
78-95% (37,48,58,66) mRNA-1273: 96% (49) mRBA-1273: 76-84% (67,68)
Effectiveness against
mRNA-1273: 84-99% mRNA-vaccines: 64% (147)
SARS-CoV-2
(49,147) mRNA-vaccines/Janssen: 47-79% NA
infection (fully
AZD1222: 79% (66) (59,81)
vaccinated)
AZD1222: 60-67% (44,66)
mRNA/AZD-1222: 49% (79)
BNT162b2n mRNA-1273: BNT162b2: 95% (38) BNT162b2: 95% (38) BNT162b2: 80% (60)
Effectiveness against
>89% (36,38,39) mRNA-1273: 95% (60)
f
COVID-19
oo
Ad26.COV1.S: 60-85% (60,61) NA
hospitalization/death
mRNA-vaccines: 95% (39,59)
(fully vaccinated)
r
-p
246
247
re
248
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B.1.427 B.1.429
SARS-CoV-2 variants B.1.525 P2 P3 B.1.526
CAL.20C
Eta Former Zeta Former Theta Iota Former Epsilon Former Epsilon
na
Q52R, A67V, 69/70del , E484K, D614G, 141/143del, E484K, L5F, T95I, D253G, S13I, W152C, S13I, W152C,
144del, E484K, D614G, V1176F N501Y, D614G, D614G, L452R, D614G L452R, D614G
ur
Key spike mutations
Q677H, F888L P681H, E1092K, A701V+(E484K or
H1101Y, V1176F S477N)
Jo
Multiple countries Philippines USA USA USA
First detection Brazil
December 2020 January 2021 December 2020 September 2020 September
NA NA NA NA +18.6 to 24% in +18.6 to 24% in
Transmission
California (148) California (148)
Risk of mortality NA NA NA NA NA NA
0 to 3.6 fold reduction 1.3 to 4 fold reduction
for BNT162b2 for BNT162b2
(149,150) (148,151,152)
Impact on post-vaccination sera
2.3 fold reduction for
(reduction in neutralization NA NA NA 1.4 to 3.3 fold 2 to 2.8 for mRNA-
BNT162b2 (122)
activity) reduction for mRNA- 1273 (132,138,151)
1273 (138,149)
4 fold reduction for 2.5 fold reduction for
CoronaVac (126) NVX-CoV2373 (132)
25
CoronaVac (126)
Effectiveness against infection NA NA NA NA NA NA
(full vaccinated)
Effectiveness against NA NA NA NA NA
hospitalization/death (full NA
vaccinated)
249
250
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SARS-CoV-2 variants B.1.621 C.37
Mu Lambda
r
R346K, E484K, N501Y, L452Q, F490S,
-p
Key spike mutations
D614G, P681H D614G
Colombia Peru
re
First detection
January 2021 December 2020
lP
Transmission NA NA
Risk of mortality NA NA
na
CoronaVac (127)
ur
1.7 to 4.6 fold
reduction for
Jo
Impact on post-vaccination BNT162b2
2 to 7.6 fold reduction for
sera (reduction in (122,150,154)
BNT162b2 (122,153)
neutralization activity) 3.3 to 4.6 fold
reduction for mRNA-
1273 (154)

Sputnik V (135)
Effectiveness against infection NA NA
(full vaccinated)
Effectiveness against NA NA
hospitalization/death (full
vaccinated)
251
26
252
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253
254 Limitations of neutralizing assays
255 Limitations concerning neutralizing assays should be underlined 1) most studies were preprints 2)
256 results are not necessarily linked to clinical consequences. However, one study based on seven
257 vaccines reported a high correlation between neutralization titers and protection estimated in Phase III
258 trials(155). A 50% protection against SARS-CoV-2 infection corresponded to a neutralization level of
259 20.2% of the mean convalescent level. 3) methods of the studies varied (pseudovirus assay, plaque
260 reduction neutralization testing, micro-neutralization assay, focus reduction neutralization test). We
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261 included 28 pseudovirus assays and 26 live virus assays. Pseudovirus assays are an approximation of
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262 authentic SARS-CoV-2 neutralization and only evaluate neutralizing antibodies on pseudoviruses with
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263 mutations on the spike protein. Additionally, the choice of cell lines and virus models (vesicular
264
-p
stomatitis virus or human immunodeficiency virus-1 for example) can impact the neutralizing activity.
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265 Pseudoviruses are surrogates and cannot complete the same life cycle as the live virus, thus it is not
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266 possible to assess the inhibitory effect on viral replication but they are used to study virus entry. Live
267 virus neutralization assay remains the gold standard but it needs a higher safety level (a biosafety level
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268 3 laboratory) 4) the time post-vaccination and study populations were not always comparable
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269 regarding age or COVID-19 history 5) T-cell responses were not assessed. Most studies on in vitro
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270 vaccine efficacy focused on the ability of the vaccine antibodies to bind to the virus which partially
271 reflect vaccine effectiveness, but cell-mediated immunity should also be considered. Studies have
272 shown BNT162b2 and Ad26.COV2.S induce CD4+ and CD8+ T cell response (94,156). Preliminary
273 reports have identified vaccine-induced CD4+ T cells 6 months after the 2nd dose of RNA-1273 (157)
274 and memory B-cells at 6 months after two doses of BNT162b2(158). SARS-CoV-2-specific memory
275 T cells and B cells are important for long-term protection. A main limitation of these studies on cell-
276 mediated immunity is the small sample size.
277 Vaccine regimens
278 Heterologous prime-boost vaccination
279 Changing recommendations for young people regarding use of AZD1222 and the need to accelerate
280 the vaccination campaign has led some countries advising heterologous prime-boost vaccination with
28
281 a second dose of mRNA vaccines. An RCT conducted in the UK indicated an increase in systemic
282 reactogenicity in a heterologous vaccination context vs homologous vaccination(159) but efficacy data
283 have not been yet published. A press communication from El Instituto de Salud Carlos III from a
284 phase II trial in Spain showed that the combination of AZD1222 and BNT162b2 induced a strong
285 humoral response when compared to no second dose(160). The Com-Cov randomized trial also
286 supported flexibility in the use of AZD1222 and BNT162b2 with a 28-days interval inducing similar
287 levels of SARS-CoV-2 anti-spike IgG (161). A preliminary study in Thailand observed an increased in
288 neutralizing antibodies against Delta after a third dose of BNT162b2 or AZD1222 among participants
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289 who received two doses of CoronaVac(162).
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290 Extension of the dose interval
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291 More generally, evidence on the extension of the interval between doses is scarce. Trials for AZD1222
292
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showed that a longer delay was better, but for mRNA and other vaccines, trials did not test different
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293 dose gaps(163). A preprint reported that extending the interval to 6 weeks for BNT162b2 vaccine led
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294 to higher titers in neutralizing antibodies and a sustained T cell response against the variants of
295 concerns (164). Another analyses found that a second dose at 12 weeks induced a stronger humoral
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296 response than at a 3-week interval among older people(165).

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297 A booster dose for specific populations

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298 Immunogenicity studies amongst transplant patients and patients with cancer showed a poor antibody
299 response after a single dose or two doses of Pfizer vaccine(166–168). Facing this issue, French,
300 German, British and the US health authorities have recommended a third dose for
301 immunocompromised people and transplant recipients. A randomized trial in transplant recipients
302 showed a third dose of mRNA-1273 was safe, and 26 out of 59 participants who had negative antibody
303 responses prior to the booster developed antibody responses after the third dose (169). However, this
304 study did not look at cellular immune response. Another study found that an additional dose of
305 mRNA-1273 induced a serologic response among 50% of kidney transplant recipients not responding
306 after two doses (170). A case-control study in preprint found an effectiveness against SARS-CoV-2
307 infection 14-20 days after the third dose increased by 79% (vs 2nd dose) (171). Another observational
308 study in Israel found a booster dose reduced the rate of confirmed infections and severe disease by a
29
309 factor of 11.3 and 19.5, respectively, among elderly participants (172). Two studies also showed
310 Moderna boosters (at least 6 months after the 2nd dose) and Pfizer booster (8-11 months after the 2nd
311 dose) induced a strong humoral response against Beta (173) and other variants of concern (174). The
312 expected local and systemic adverse events were mild and moderate and similar to those after the 2 nd
313 dose.
314 Vaccination of previously infected individuals
315 Several neutralization assays have suggested that a single dose of BNT16b or mRNA-1273 among
316 previously infected subjects could boost the cross-neutralization response against emerging variants
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317 such as Alpha, Beta or Gamma (121,175). These studies have demonstrated the potential benefits of
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318 vaccinating both non-infected and previously infected people. Finally, several studies suggested that a
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319 single dose of mRNA vaccine may be sufficient to boost the antibody response in previously infected
320
-p
subjects and that the benefit of the second dose may be small (176–180).
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321
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322
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323 Severe adverse events
324 Main severe adverse events reported in pharmacovigilance systems and post-authorization studies are
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325 summarized in Table 4. Among adults, the main severe adverse events reported were very rare:
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326 anaphylaxis (2.5-4.8 cases per million doses among adults) and myocarditis (6-27 cases per million)
327 for mRNA vaccines ; thrombosis with thrombocytopenia syndrome for Janssen vaccine (3 cases per
328 million) and AstraZeneca vaccine (2 cases per million) and Guillain-Barré syndrome (GBS) (7.8 cases
329 per million) for Janssen vaccine. For AZD1222, capillary leak syndrome was also identified as a
330 possible adverse effect and multisystem inflammatory syndrome is under investigation. The EMA
331 excluded an association between AZD1222 and menstrual disorders (181).
332
333 Occurrence of adverse events changed with age. Myocarditis associated to mRNA vaccination were
334 mainly identified among males aged <30 years with 39-47 cases per million vaccine doses in the USA
335 (vs 3-4 myocarditis expected among male aged ≥30 years) (182). On April 23, the EMA estimated 2
30
336 cases of thrombosis with thrombocytopenia (TTS) associated with AZD1222 per 100,000 doses for
337 people aged 20-49 years old, 1 case/100,000 doses for those aged 50-69 years old and even lower case
338 rates (< 1/100,000 doses) for older people. Similarly, the case-rate of TTS was higher for Janssen
339 vaccine among young women. Surveillance studies found rare cases of Bell’s palsy (3.8 cases per
340 100,000), anaphylaxis (2 cases per million), thromboembolic event (1.2 cases per million), GBS (0.29
341 cases per million) for CoronaVac. Several observational and survey studies with low sample size did
342 not find specific severe adverse events for Sputnik V, BBIBP-COrV, Covaxin. Studies on adverse
343 events were lacking for CIGB-66, QazVac, COVIran, Barkat, ZF2001, EpiVacCorona. Pregnant
f
344 women were excluded from clinical trials but surveillance systems did not report an excess of adverse
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345 pregnancy and neonatal events after mRNA vaccination (183,184) while an increased risk of severe
r
346 COVID-19 in pregnancy and babies’ admission in the neonatal unit was consistently observed (185).
-p
re
lP
na
ur
Jo
31
347 Table 4: Main severe adverse events following COVID-19 vaccination in observational studies and pharmacovigilance systems
Cases per
Number of participants or
Vaccine Serious adverse events million doses Country Age Follow-up References
doses studied
administered
11,8 million doses Klein et al.
December 14, 2020, to
Anaphylaxis 4.8/million USA administered (57% (186)
12 years June 26, 2021
BNT162b2) to 6.2 million
individuals
476 cases MHRA (Yellow
Anaphylaxis + 16 years December 9, 2020 to
f
among 40 UK 40 million doses (1 and 2) Card Scheme)
oo
anaphylactoid reactions September 1, 2021
million doses (187)
Myocarditis 2.7/100,000
r
BNT162b2 Lymphadenopathy 78.4/100,000 16 years December 20, 2020 to 1,736,832 participants Barda et al.
-p
Israel
Appendicitis 5/100,000 May 24, 2021 (884,828 vaccinated) (188)
Herpes zoster infection 15.8/100,000
re
Bell’s palsy 2.6/100,000
Hongkong Hongkong Drug
lP
Myocarditis/Pericarditis 0.86/100,000 12 years Up to 31 August 4,776,700 doses
Office (189)
Transverse myelitis 0.01/100,000
6/million MHRA (Yellow
na
Myocarditis 16 years December 9, 2020 to
4.9/million UK 40 million doses (1 and 2) Card Scheme)
Pericarditis September 1, 2021
(187)
5.1/million
urUSA December 14, 2020, to
11,8 million doses
administered (43% mRNA-
Klein et al.
Jo
(186)
12 years June 26, 2021 1273) to 6.2 million
Anaphylaxis individuals
mRNA-1273
16 years December 21, 2020 to
2.5/million USA 4,041,396 doses US CDC (190)
January 10, 2021
MHRA (Yellow
Myocarditis 20.4/million 18 years December 9, 2020 to
UK 2.3 million doses (1 and 2) Card Scheme)
Pericarditis 14.8/million September 1, 2021
(187)
Curevac Not authorized
Retrospective survey of 75 Rajpurohit et al.
Thromboembolic events 0.61/million India 18 years Date not specified
random subjects (191)
AZD1222 Thrombosis with 14.9/million 18 years MHRA (Yellow
December 9, 2020 to
thrombocytopenia 20.5/million UK 18-49 48,9 million doses (1 and 2) Card Scheme)
September 1, 2021
syndrome (187)
32
Capillary Leak Syndrome 12 cases 18 years
among 48,9
million doses
Myocarditis
Pericarditis 2.1/million
Anaphylaxis or 3.3/million
anaphylactoid reactions 816 cases
among 48.9
million doses
833 cases
f
oo
Guillain-Barré syndrome among 592 Worldwide 18 years By 25 July 2021 592 million doses EMA (181)
million doses
Thrombosis with 1,503 cases
r
-p
thrombocytopenia among 592 Worldwide 18 years By 25 July 2021 592 million doses EMA (181)
syndrome million doses
re
45 cases for
Thrombosis with
14.3 million
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thrombocytopenia
doses
syndrome 18 years
Janssen (3/million) USA As of September 1, 2021 14.3 million doses US CDC (192)
na
185 cases for
Guillain-Barré Syndrome
14.3 millions
expected local and 2.1%
ur
Jo
systemic reactions participants
Republic of
The most frequent suffered severe 18-89 years Montalti et al.
San Marino 4 March to 8 April 202 Cohort of 2 558 participants
symptoms were local pain, reactions in (193)
Sputnik V asthenia, headache, and San Marino’s
joint pain population
5% of serious
Pagotto et al.
adverse events Argentina 18-80 years January 5 to 20, 2021 707 participants
(194)
(n=34)
NVX-
Not authorized
CoV2373
EpiVacCorona We did not find any comparative studies addressing post-authorization safety
ZF2001 We did not find any comparative studies addressing post-authorization safety
Convidecia We did not find any comparative studies addressing post-authorization safety
CoronaVac Bell’s palsy 3.8/100 000 Hong Kong 12 years Up to 31 August N=2,811,500 doses Hongkong Drug
33
Encephalopathy 0.01/100 000 Office (189)
Anaphylaxis 2/million Instituto de Salu
Thromboembolic events 1.15/million 16 years December 24, 2020 to Publica de
Chile N=13,862,155 doses
Bell’s palsy 8.73/million May 14, 2021 Chile (ISP)
Guillain-Barré Syndrome 0.29/million (195)
- Mean age: 35-
No serious side effects Retrospective survey of 409 Abu-Hammad
Jordan 40 years No date specified
were reported. participants et al. (196)
BBIBP-COrV
- Retrospective cross-
No severe side effects were 18 years Almufty et al.
Iraq April 2021 sectional study of 1,012
reported. (197)
participants
f
oo
-
Indian Ministry of Health
- Indian Ministry
and Family Welfare and a
of Health and
r
retrospective cohort 18 years
-p
Covaxin India No date specified Family Welfare
reported no serious adverse
Rajpurohit et al.
effects associated to
re
Retrospective survey of 75 (191)
Covaxin
random subjects
lP
CIGB-66 We did not find any comparative studies addressing post-authorization safety
QaeVac We did not find any comparative studies addressing post-authorization safety
na
COVIran
We did not find any comparative studies addressing post-authorization safety
Barkat
ur
348 Jo
349
350
351
34
352
353 Limitations of this review
354 This review presents several limitations. Several analyses were not peer-reviewed and only press
355 communications or regulatory market authorization files were available for CoronaVac, BBIBP-CorV,
356 Wuhan inactivated vaccine, Covaxin and NVX-CoV2373. Clinical trials used different definitions for
357 COVID-19 and different primary endpoints which make direct comparisons difficult. Janssen’s
358 primary endpoint is moderate/severe/critical COVID-19 whereas Pfizer and Moderna included mild
359 COVID-19. The endpoint time was also heterogeneous across trials, but most trials used 14 days after
f
360 the full immunization.
oo
361 Observational studies, unlike randomized studies, cannot guarantee comparability in the exposition of
r
362 different populations to SARS-CoV-2 and to the variants of concern. Indeed, real world studies
363
-p
present large variations in time post-vaccination, exposition to SARS-CoV-2 strain, susceptibility to
re
364 infection (previously infected or not), study population (healthcare workers, older adults,
lP
365 immunocompromised, chronical medical conditions, etc.). Moreover, due to a lack of randomization,
na
366 observational studies are subject to bias when assessing effectiveness, such as misclassification from
367 diagnostic errors, imbalances in socioeconomic status, exposure risk, health care seeking behaviours,
ur
368 or immunity status between vaccinated and unvaccinated groups. Not all the observational studies
Jo
369 used adjustments to take into account confounding biases. For example, healthcare workers treating
370 COVID-19 patients may be more frequently exposed to SARS-CoV-2, leading to decreased estimates
371 of effectiveness. Various designs (cohort, case-control study, test-negative design (TND)) were used
372 in observational studies, each of them having limitations. Cohorts require large sample size for
373 uncommon outcomes (i.e. severe COVID-19) but vaccination status may be more difficult to
374 determine in retrospective cohorts. In case-control studies, vaccinated people may be more likely to
375 seek health care and SARS-CoV-2 testing, biasing toward a reduction in the estimation of
376 effectiveness.
377
378 Conclusion
35
379 To date, the availability of data varies greatly depending on the vaccine considered. mRNA vaccines,
380 AZD1222, Ad26.COV2.S, Sputnik V, NVX-CoV2373, Ad5-nCoV, BBIBP-COrV, CoronaVac,
381 COVAXIN and Wuhan inactivated vaccine showed an efficacy against COVID-19 over 50% in Phase
382 III studies. Most observational studies assessed the mRNA vaccines, CoronaVac and AZD1222 which
383 appear to be safe and highly effective tools to prevent severe disease, hospitalization and death against
384 all variants of concern (Alpha, Beta, Gamma and Delta). Large observational studies were lacking for
385 several authorized vaccines: Sputnik V, Sputnik V Light, BBIBP-CorV, COVAXIN, EpiVacCorona,
386 ZF2001, Abdala, QazCovid-In, Wuhan Sinopharm inactivated vaccine, KoviVac and COVIran
f
387 Barekat. The protection against symptomatic and asymptomatic infection was high for Alpha, Beta
oo
388 and Gamma for mRNA-vaccines and AZD1222. mRNA vaccines and Ad26.COV2.S were associated
r
389 with a faster decline in viral load against several variants including Delta and a lower probability of
390
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viral culture positivity. Effectiveness against infection and COVID-19 declined following infection
re
391 with the Delta variant and over time, possibly due to a waning of immunity.
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392 Heterologous prime-boost vaccination and a third dose of vaccine both induced a strong humoral
393 response. Vaccinating previously infected people with a single dose provided an equivalent
na
394 neutralizing response compared to people vaccinated with two doses against all the variants.
ur
395 According to safety monitoring, reported serious adverse events were very rare and the benefits of
Jo
396 COVID-19 vaccination far outweighed the potential risks.
397 More research is needed considering booster doses, heterologous vaccination, dosing intervals,
398 vaccine breakthrough infections and duration of vaccine immunity against variants of concern.
399
400 Competing interests and funding sources
401 All authors declare: no support from any organization for the submitted work; no financial
402 relationships with any organizations that might have an interest in the submitted work in the previous
403 three years; no other relationships or activities that could appear to have influenced the submitted
404 work.
36
405 Thibault Fiolet received a PhD grant from the Fondation pour la Recherche Médicale (FRM)
406 n°ECO201906009060. This funder had no role in study design, data collection and analysis, decision
407 to publish, or preparation of the manuscript.
408
409 Authorship statement
410 TF and NPS designed and conducted the research. TF wrote the first draft of the paper. All authors
411 (TF, YK, CJM, JG, NPS) contributed to the data interpretation, revised each draft for important
412 intellectual content, and read and approved the final manuscript.
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413 References
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Figure List and legend
Fig 1: Vaccine efficacy against 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
Fig 2: Vaccine effectiveness against SARS-CoV-2 asymptomatic or symptomatic infection from

real world studies (in % and 95%CI) according to the number of doses.
Fig 3: Vaccine effectiveness against SARS-CoV-2 hospitalization or death from real world
studies (in % and 95%CI) according to the number of doses.
f
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Fig 4: Vaccine effectiveness against 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
r
refers to Alpha, Beta, Delta, Gamma and not sequenced strain, respectively.
-p
Fig 5: Average fold reduction in neutralizing response against SARS-CoV-2 variant versus wild
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type/D614G SARS-CoV-2 for each 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 boxplot
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included different methods assessing neutralizing antibodies titers. Methods are detailed in the
supplementary table S2.
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List of Tables
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Table 1: Characteristics of COVID-19 vaccines

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Table 2: Phase III Trials for COVID-19 vaccines
Table 3: COVID-19 vaccines and variants
Table 4: Main severe adverse effect following COVID-19 vaccination in observational studies
and pharmacovigilance systems
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Comparing COVID 19 Vaccines For Their Characteristics, Efficacy

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Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness

Thibault Fiolet, Yousra Kherabi, Conor-James MacDonald, Jade Ghosn, Nathan

To appear in: Clinical Microbiology and Infection

Received Date: 3 August 2021

2 SARS-CoV-2 and variants of concern: A narrative review

8 UMR1018, Villejuif, France

14 Infections and Antimicrobial Resistance, Imperial College, London, UK

21 Abstract: 295 words

22 Manuscript: 3552 words

57 despite rare serious adverse effect.

69 when compared to the original strain or D614G variant (7–11).

74 asymptomatic infection and the severity of COVID-19.

83 AZD1222, Sputnik V, Sputnik V Light, Ad5-nCoV (Convidecia), Ad26.COV2.S ; inactivated

85 Covaxin, QazVac, KoviVac, COVIran Barekat ; protein-based vaccine: EpiVacCorona, ZF2001,

90 using the search terms “SARS-CoV-2”, “COVID-19”, “efficacy”, “effectiveness”, “neutralization

102 infection, COVID-19, hospitalization or mortality.

108 Evidence on vaccine efficacy and effectiveness

121 NA, not available information

122 EU, European Union

ur encoding the SARS-CoV-2 Spike

125 *Prices were retrieved from

132 Messenger RNA (mRNA) Vaccines

147 Inactivated and protein subunit vaccines

149 made of fragments of proteins or polysaccharides. NVX-COV2373 had an efficacy of 89-91.6%

159 NA, not available information

Vaccin Any unsolicited

follow-up: 81.5% (67.9

Colombia, the vaccine

Pakistan, COVID-19 disease

CanSino 8 February, 68.83% NA NA 95.47% NA NA NA

Mexico, 14 days after single

Bharat COVID-19, 14 days

Biotech( after the second NA NA NA NA NA

164 Table 2. Most studies have a follow-up of 90 days post-vaccination.

166 Effectiveness against COVID-19 (symptomatic infection)

182 full immunization (36,38,39,43,48,56,59,62,63).

183 Effectiveness against asymptomatic SARS-CoV-2 infection

194 Impact on viral load, infectivity, transmission and long COVID

210 two doses) (93).

2.9 fold reduction for

254 Limitations of neutralizing assays

276 mediated immunity is the small sample size.

277 Vaccine regimens

278 Heterologous prime-boost vaccination

296 response than at a 3-week interval among older people(165).

297 A booster dose for specific populations

314 Vaccination of previously infected individuals

323 Severe adverse events

331 excluded an association between AZD1222 and menstrual disorders (181).

353 Limitations of this review

380 AZD1222, Ad26.COV2.S, Sputnik V, NVX-CoV2373, Ad5-nCoV, BBIBP-COrV, CoronaVac,

396 COVID-19 vaccination far outweighed the potential risks.

400 Competing interests and funding sources

407 to publish, or preparation of the manuscript.

409 Authorship statement

419 of SARS-CoV-2 lineage B.1.1.7 in England. Nature. 25 mars 2021;1‑17.

425 5. Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. Risk of

431 7. Planas D, Bruel T, Grzelak L, Guivel-Benhassine F, Staropoli I, Porrot F, et al. Sensitivity of

499 Vector). 24 févr 2021; Disponible sur:

503 sur: http://www.sinovac.com/?optionid=754&auto_id=922

505 an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-

543 Clin Microbiol Infect Dis. 12 juill 2021;S1198-743X(21)00379-7.