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RESEARCH ARTICLES

Cite as: P. B. Gilbert et al., Science


10.1126/science.abm3425 (2021).

Immune correlates analysis of the mRNA-1273 COVID-19


vaccine efficacy clinical trial
Peter B. Gilbert1,2,3*†, David C. Montefiori4†, Adrian B. McDermott5†, Youyi Fong1,2, David Benkeser6, Weiping
Deng7, Honghong Zhou7, Christopher R. Houchens8, Karen Martins8, Lakshmi Jayashankar8, Flora Castellino8,
Britta Flach5, Bob C. Lin5, Sarah O’Connell5, Charlene McDanal4, Amanda Eaton4, Marcella Sarzotti-Kelsoe4,
Yiwen Lu1, Chenchen Yu1, Bhavesh Borate1, Lars W. P. van der Laan1, Nima S. Hejazi1,9, Chuong Huynh8,
Jacqueline Miller7, Hana M. El Sahly10, Lindsey R. Baden11, Mira Baron12, Luis De La Cruz13, Cynthia Gay14,
Spyros Kalams15, Colleen F. Kelley16, Michele P. Andrasik1, James G. Kublin1, Lawrence Corey1,17, Kathleen M.
Neuzil18, Lindsay N. Carpp1, Rolando Pajon7, Dean Follmann19, Ruben O. Donis8‡, Richard A. Koup5‡, on behalf
of the Immune Assays Team§, Moderna, Inc. Team§, Coronavirus Vaccine Prevention Network
(CoVPN)/Coronavirus Efficacy (COVE) Team§, and United States Government (USG)/CoVPN Biostatistics
Team§
1Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 2Public Health Sciences Division, Fred Hutchinson Cancer Research

Center, Seattle, WA, USA. 3Department of Biostatistics, University of Washington, Seattle, WA, USA. 4Department of Surgery and Duke Human Vaccine Institute, Duke
University Medical Center, Durham, NC, USA. 5Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD,
USA. 6Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA. 7Moderna, Inc., Cambridge, MA, USA.
8Biomedical Advanced Research and Development Authority, Washington, DC, USA. 9Division of Biostatistics, School of Public Health, University of California Berkeley,

Berkeley, CA, USA. 10Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. 11Brigham and Women’s Hospital, Boston, MA, USA.
12Palm Beach Research Center, West Palm Beach, FL, USA. 13Keystone Vitalink Research, Greenville, SC, USA. 14Department of Medicine, Division of Infectious Diseases,

UNC HIV Cure Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. 15Division of Infectious Diseases, Department of Medicine,
Vanderbilt University Medical Center, Nashville, TN, USA. 16Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine and the Grady
Health System, Atlanta, GA, USA. 17Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. 18Center for Vaccine Development and
Global Health, University of Maryland School of Medicine, Baltimore, MD, USA. 19Biostatistics Research Branch National Institute of Allergy and Infectious Diseases, National

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Institutes of Health, Bethesda, MD, USA.
*Corresponding author. Email: pgilbert@fredhutch.org
†These authors contributed equally to this work. ‡These authors contributed equally to this work. §The members of the Immune Assays Team; Moderna, Inc. Team;
CoVPN/COVE Team; and USG/CoVPN Biostatistics Team and their affiliations are listed in the supplementary materials.

In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing
and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These
immune markers were measured at second vaccination and 4 weeks later, with values reported in
standardized WHO International Units. All markers were inversely associated with COVID-19 risk and
directly associated with vaccine efficacy. Vaccine recipients with post-vaccination 50% neutralization
titers 10, 100, and 1000 had estimated vaccine efficacy of 78% (95% confidence interval 54, 89%), 91%
(87, 94%), and 96% (94, 98%), respectively. These results help define immune marker correlates of
protection and may guide approval decisions for mRNA COVID-19 vaccines and other COVID-19 vaccines.

Based on their demonstrated efficacy to prevent coronavirus more transmissible viral variants, highlight the need for a
disease 2019 (COVID-19) in phase 3 clinical trials, to date large armamentarium of safe and effective COVID-19
seven COVID-19 vaccines have been granted an Emergency vaccines (4, 5).
Use Listing by the World Health Organization (WHO) (1), The Coronavirus Efficacy (COVE) phase 3 trial
three have been granted an Emergency Use Authorization (NCT04470427) of the mRNA-1273 COVID-19 vaccine, which
(EUA) by the US Food and Drug Administration (FDA) (2), is being conducted in the United States in adults aged 18 and
and one has been formally approved by the FDA (3). over, showed estimated vaccine efficacy against COVID-19 of
However, the manufacturing challenges posed by the global 94% in the primary analysis (6). These efficacy data sup-
demand for doses, the need for affordable and accessible ported the US Food and Drug Administration’s EUA of
options that are safe and effective in diverse populations, the mRNA-1273 for prevention of COVID-19 in adults (7). The
current lack of efficacy data in certain populations (e.g., mRNA-1273 vaccine has been shown to be highly effective in
pediatrics, pregnant women, autoimmune or the elderly and in essential and frontline workers, including
immunocompromised individuals), and the emergence of healthcare workers (8), and to have non-inferior binding and

First release: 23 November 2021 science.org (Page numbers not final at time of first release) 1
neutralizing antibody responses in adolescents vs. adults (9). future analyses of how the current level of antibody correlates
Correlates of protection, which are immunological mark- with instantaneous risk of COVID-19. Such analyses may in-
ers that can be used to reliably predict the level of vaccine form how vaccine efficacy wanes as antibody levels wane and
efficacy against a clinically relevant endpoint such as COVID- as new variants emerge, which in turn may inform decisions
19 (10–12), are highly sought in vaccine research. The identi- about the timing of a potential third dose of vaccination
fication and validation of a correlate of protection would ex- and/or the need to update vaccine composition (26).
pedite the clinical evaluation and regulatory approval process
for existing vaccines for new populations, for vaccine regimen Antibody marker levels are lower in vaccine recipient
modifications, and for new vaccines. Neutralizing antibodies cases versus non-cases
(nAbs) or binding antibodies (bAbs) have been established as At Day 57, almost 100% of vaccine recipients had positive/de-
a correlate of protection for vaccines against many viral dis- tectable antibody response by all four markers (Table 1; table
eases (11). The hypothesis that antibodies, whether elicited by S3 shows assay limits for each marker). This was also true at
infection or by spike protein-based vaccines, are a correlate Day 29 for spike IgG and RBD IgG, whereas ID50 and ID80
of protection against COVID-19 is supported by diverse lines titers were detectable in 82% and 64% of vaccine recipients,
of evidence (13–25). For the mRNA-1273 vaccine, multiple se- respectively. Each marker was moderately correlated be-
vere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tween the Day 29 and Day 57 time points (Spearman rank r
antibody markers including IgG bAbs to the spike protein, = 0.53 to 0.62; fig. S4). Together the spike IgG and RBD IgG
IgG bAbs to spike receptor binding domain (RBD), and 50% markers were tightly correlated (Spearman rank r = 0.94, 0.97
(ID50) inhibitory dilution nAb titer, each correlated with pro- at Day 29, 57; figs. S5 and S6), as were the ID50 and ID80
tection against SARS-CoV-2 replication after challenge in vac- markers (r = 0.97, 0.96 at Day 29, 57; figs. S5 and S6). Accord-
cinated rhesus macaques (24). Here we assessed these same ingly, some results focus on spike IgG and ID50. Each binding
SARS-CoV-2 antibody markers, and in addition, 80% inhibi- antibody marker was correlated with each neutralization
tory dilution (ID80) nAb titer, as correlates of risk of COVID- marker at each time point (r = 0.73 to 0.80).
19 and as correlates of mRNA-1273 vaccine protection against Figure 1 and fig. S7 show the Day 29 and Day 57 marker
COVID-19 in the COVE trial. distributions by case/non-case status in vaccine recipients

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(fig. S8 in placebo recipients); figs. S9 and S10 show marker
Results values by participant age. For all eight markers the geometric
mean was lower in vaccine breakthrough cases than in vac-
Participant demographics
cine recipient non-cases, with geometric mean ratios
Table S1 describes demographics of the randomly sampled
(cases/non-cases) and their 95% CI upper bounds all lower
immunogenicity subcohort (N = 1010 vaccine, N = 137 pla-
than one (Table 1).
cebo). Thirty-four percent of baseline SARS-CoV-2 negative
Figures S11 and S12 show reverse cumulative distribution
per-protocol participants were age 65 or over, 40% were
function curves of the eight markers, in the context of the
deemed to be at risk for severe COVID-19 illness (“at risk”),
overall vaccine efficacy estimates (27). Figure S13 shows the
47% were assigned female sex at birth, 32% were Hispanic or
Day 29 and/or Day 57 marker values of vaccine breakthrough
Latino, 46% White and Non-Hispanic, and 54% communities
cases by timing of COVID-19 endpoint diagnosis.
of color, with 18% Black or African American. Table S2 and
figs. S1 and S2 describe the ‘Day 29 marker case-cohort set’
COVID-19 risk of vaccine recipients decreases as anti-
and the ‘Day 57 marker case-cohort set’, which augment the
body marker level increases
immunogenicity subcohort with all vaccine breakthrough
Figure 2 shows Cox model-based covariate-adjusted COVID-
COVID-19 endpoint cases and comprise the sets of partici-
19 cumulative incidence curves for subgroups of vaccine re-
pants included in the analyses of antibody markers measured
cipients defined by tertile of Day 57 IgG spike or ID50 (Fig. 2,
at Day 29 or Day 57 as correlates, respectively.
A and B). Corresponding results for IgG RBD and ID80 are
shown in fig. S14. (Details on covariate adjustment are given
COVID-19 endpoints
in supplementary text, section S1; tables S4 to S7; and figs.
Analyses of Day 29 and Day 57 antibody markers as correlates
S15 and S16.) Multiplicity-adjusted p-values indicated signifi-
included vaccine breakthrough COVID-19 endpoints starting
cant inverse correlations with risk, with estimated hazard ra-
7 days post Day 29 (n=46) and post Day 57 (n=36), respec-
tios for upper vs. lower tertiles ranging between 0.20 and 0.31
tively (fig. S3). Average follow-up of vaccine recipients was
(Fig. 2C). For quantitative Day 57 markers, the estimated haz-
116 days post Day 29 and 88 days post Day 57. All immune
ard ratio per 10-fold increase in marker value ranged between
correlates analyses were prespecified as detailed in the Sta-
0.35 and 0.66 (Fig. 3A), with multiplicity-adjusted p-values
tistical Analysis Plan (SAP).
indicating significant associations. Generally, similar results
Note that COVE follows participants for 2 years, enabling

First release: 23 November 2021 science.org (Page numbers not final at time of first release) 2
were obtained across pre-specified vaccine recipient sub- = 22% vs. 4%). Vaccine efficacy estimates also increased with
groups (Fig. 3, B and C, and fig. S17). Day 29 ID50 neutralization titers: 79% (−62, 90%), 93% (90,
The four markers at Day 29 were also significant inverse 95%), 97% (95, 99%), and 99 (97, 100%) at the same IU50/ml
correlates of risk, with estimated hazard ratios for upper vs. values (fig. S22).
lower tertiles ranging between 0.19 and 0.32 (figs. S18 and Figures S23 to S28 show these results for the other six an-
S19), and estimated hazard ratios per 10-fold increase in tibody markers. Conclusions for binding antibodies were sim-
marker value ranging between 0.19 and 0.54 (fig. S17). P-val- ilar to those for neutralizing antibodies, with vaccine efficacy
ues were smaller for Day 29 than Day 57 markers indicating increasing with IgG levels, for example at Day 57 spike IgG of
strengthened evidence for correlates of risk. If a Day 29 im- 33, 300, and 4000 BAU/ml, vaccine efficacy was 85% (31,
mune marker in recipients of two mRNA-1273 doses becomes 92%), 90% (77, 94%), and 94% (91, 96%), respectively. An-
established as a correlate of protection, it could be a more other conclusion of these analyses is that subgroups with
practical surrogate marker than a Day 57 marker. Of note, all neutralization titer 10 IU50/ml (Fig. 4C) or with anti-spike
participants in our correlates analysis received both dose 1 IgG 33 BAU/ml (fig. S24C) have about 75-85% reduction in
and dose 2, and thus the Day 29 correlates results reflect the COVID-19 risk compared to being unvaccinated. Given the
full effect of the two vaccine doses used in clinical practice. overall similarity of the binding antibody and neutralizing
The estimated cumulative incidence of COVID-19 by end antibody correlate of protection results, the potential value of
of blinded follow-up (100 days post Day 57) for the entire vac- the validated MSD binding antibody assay for aiding vaccine
cine group was 0.0033 (95% CI 0.0022, 0.0045). Based on approval decisions as a practical non-mechanistic CoP (12)
nonparametric threshold regression this cumulative inci- should be considered. This is because the MSD binding anti-
dence decreased across vaccinated subgroups with Day 57 body assay is sensitive (table S3), robust, high-throughput,
ID50 titer above a given threshold, with zero COVID-19 end- deployable and easily standardized across viral strains, even
points at ID50 titer above 1000 IU50/ml (Fig. 4A). The shape though validated sensitive binding antibody detection may
of cumulative incidence across threshold subgroups tracked lack the specific immune function such as neutralization.
the reverse cumulative distribution function of ID50 titer,
suggesting a smooth incremental change in risk with titer A sensitivity analysis further increases confidence that

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(Fig. 4A). Based on the Cox model, Fig. 4B showed estimated vaccine efficacy increases with antibody marker levels
cumulative incidence of COVID-19 by end of blinded follow- A sensitivity analysis was conducted (supplementary text,
up across vaccinated subgroups with Day 57 ID50 titer at spe- section S2) assuming the existence of an unmeasured con-
cific titers, in contrast to Fig. 4A that considered vaccinated founder associated with both the antibody marker and
subgroups with titers above specific values. For vaccine recip- COVID-19 outcome that would make the estimated vaccine
ients with undetectable Day 57 ID50 titer, estimated cumula- efficacy by marker curve flatter, with specified amount of un-
tive incidence was 0.030 (0.010, 0.093), and decreased to measured confounding detailed in the SAP (Section 12.1.2).
0.014 (0.0067, 0.028) at titer of 10, to 0.0056 (0.0039, 0.0080) The analysis indicated that vaccine efficacy estimates still in-
at titer of 100, and to 0.0023 (0.0013, 0.0036) at titer of 1000 creased with Day 57 ID50 titer [90% (69, 96%) at undetecta-
(Fig. 4B). The generalized additive model also supported in- ble Day 57 ID50 titer, 95% (93, 97%) at Day 57 ID50 titer of
verse correlates of risk for all markers (figs. S20 and S21). 500, and 96% (93, 97%) at Day 57 ID50 titer of 1000] (fig.
S29C). A similar pattern of results occurred for all other neu-
Vaccine efficacy increases as antibody marker level in- tralizing antibody markers (fig. S29D and fig. S30, C and D).
creases In contrast, estimated vaccine efficacy appeared to vary only
Figure 4C shows ‘titer-specific vaccine efficacy’ across Day 57 minimally with each binding antibody marker when unmeas-
ID50 titer levels, which for a given titer level is the estimated ured confounding was assumed (fig. S29, A and B, and fig.
covariate-adjusted percent reduction in cumulative incidence S30, A and B). The sensitivity analysis based on E-values (29)
of COVID-19 by the end of blinded follow-up due to vaccina- of the vaccine recipient antibody tertile subgroups (supple-
tion generating the given titer level compared to being un- mentary text, section S2) supported the inference that vac-
vaccinated (28). Vaccine efficacy estimates increased with cine efficacy was generally higher for the upper vs. lower
Day 57 ID50 titer: At undetectable Day 57 ID50, vaccine effi- tertile subgroup (table S8), suggesting that vaccine efficacy
cacy was 51% (−51, 83%), and at Day 57 ID50 value of 10, 100, would have still increased with each antibody marker level
and 1000 IU50/ml, respectively, vaccine efficacy was 78% (54, even if additional (hypothetical) unmeasured confounders
89%), 91% (87, 94%), and 96% (94, 98%) (Fig. 4C). The in- had been present.
crease in vaccine efficacy from 78% to 96% at ID50 values of Given the overlap of marker distributions in vaccine
10 to 1000 IU50/ml, respectively, represents a 5.5-fold in- breakthrough cases and vaccine recipient non-cases (Fig. 1
crease in vaccine-risk reduction (one minus vaccine efficacy and fig. S7), our results do not support that a Day 29 or Day

First release: 23 November 2021 science.org (Page numbers not final at time of first release) 3
57 antibody marker could be highly effective in guiding indi- against virologically confirmed influenza B/Victoria illness
vidual decisions of whether to be re-vaccinated or boosted. (31). As hemagglutination inhibition titer has been used to
Yet, if a vaccinated person has negative IgG response or un- guide influenza vaccine strain selection and approval, this de-
detectable neutralization response, based on our results it fines a potential benchmark for influencing COVID-19 vac-
would be rational for this person to be concerned about rela- cine approval decisions (32).
tively weak protection and hence prompting seeking out A possible interpretation also consistent with our results
other means of protection. is that neutralization as a biological function mediated a
large proportion of the vaccine efficacy, but the specific Day
Neutralizing antibodies mediate about two-thirds of the 29 ID50 and ID80 immune markers studied, measured with
mRNA-1273 vaccine efficacy a particular immunoassay, had inadequate sensitivity to
For binding antibodies at both time points, and for neutral- quantify low-level neutralization below the positivity cutoff
izing antibodies at Day 57, a challenging issue is understand- that could be present and functionally important. Passive
ing vaccine efficacy for vaccine recipients with transfer of purified IgG from mRNA-1273-immunized rhesus
negative/undetectable antibody level, given that fewer than macaques protected golden Syrian hamsters from disease af-
2% of vaccine recipients had negative or undetectable anti- ter SARS-CoV-2 challenge, suggesting functionally active an-
bodies. Consequently, the 95% confidence intervals about tibodies can mediate protection (24). However, additional
vaccine efficacy for these subgroups were wide and assess- immune markers are likely needed to fully explain the ob-
ment of mediation through these markers was not technically served vaccine efficacy in COVE, for example markers meas-
possible because of insufficient overlap of marker values in uring additional immune functions beyond neutralization
placebo and vaccine recipients. However, Day 29 ID50 and (e.g., Fc effector functions or functional T cells), markers not
ID80 titers could be assessed as mediators of vaccine efficacy measured fully in serum (e.g., mucosal), and/or anamnestic
by the Benkeser et al. method (30), given that 18% and 36% responses not fully represented by a single time point meas-
of vaccine recipients had undetectable titer, respectively, urement.
providing enhanced precision [e.g., estimated vaccine effi- Further clarification of functional mediation of protection
cacy 79% (95% CI 62, 90%) at undetectable ID50]. The quan- may be provided by future correlates analyses that study an-

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titative ID50 and ID80 variables were studied. An estimated tibody markers over time in relation to the timing of break-
68.5% (58.5, 78.4%) of vaccine efficacy was mediated by Day through infections of variants with variable neutralization
29 ID50 titer and 48.5% (34.5, 62.4%) by Day 29 ID80 titer sensitivity, with the antibodies measured against the variants
(table S9). of concern as well as against the ancestral strain. In particu-
This result of positive vaccine efficacy for the undetecta- lar, future research in COVE aims to measure binding and
ble subgroup implies lack of full mediation of vaccine efficacy neutralizing antibodies to the delta variant in the same im-
through the Day 29 antibody marker (28), with an estimated munogenicity subcohort as examined in the current study,
68% of the overall vaccine efficacy mediated through Day 29 and in all additional vaccine breakthrough cases that occur
ID50 titer. Therefore if neutralizing antibodies circulating on during follow-up. This should enable analyses to assess con-
Day 29 could be removed but the other consequences of vac- sistency of an ancestral-strain correlate of protection for an-
cination remained, overall vaccine efficacy would be expected cestral-strain COVID-19 compared to a delta-variant correlate
to be reduced by 68% (on the log scale), from 92% to 56%. of protection against delta-variant COVID-19.
However, because more than 98% of vaccine recipients
achieved detectable neutralizing antibodies by Day 57, these Similar results are seen in a cross-trial/platform com-
Day 29 mediation results themselves do not reflect a com- parison
plete deactivation of the neutralizing antibody response to Our use of validated assays, with all results reported in WHO
the level at both Day 29 and Day 57 (undetectable) that would International Units or calibrated to WHO International
have been obtained without vaccination. Yet, under the rea- Standards, enables comparison with other studies and vac-
sonable assumption that the vaccine’s effect on the risk of cine platforms. Immune correlates results for the COV002
COVID-19 operating through the Day 57 ID50 marker is trial (33), which is testing the AZD1222 chimpanzee adenovi-
nonnegative, 68% is a lower bound for the proportion of vac- ral-vectored vaccine (also called ChAdOx1 nCoV-19), are avail-
cine efficacy that is mediated through ID50 at both Day 29 able (19). The COV002 correlates results for spike IgG and
and Day 57 (see conditions in supplementary text, section S2). RBD IgG can be quantitatively compared to the COVE results
In comparison, hemagglutination inhibition titer against the by virtue of the same MSD assay platform, conversion of IgG
B/Brisbane/60/2008-like (Victoria lineage) strain of influ- concentration to WHO International Units/ml, and the same
enza virus (included in the trivalent inactivated influenza antibody measurement time: 4 weeks post second dose. Esti-
vaccine) mediated an estimated 57% of vaccine efficacy mated AZD1222 vaccine efficacy was 70% and 90% at spike

First release: 23 November 2021 science.org (Page numbers not final at time of first release) 4
IgG levels of 113 (95% CI < LOD = 0.31, 245) and 899 (369, model where COVID-19 risk decreased incrementally with in-
NC) BAU/ml, respectively, and at RBD IgG levels of 165 (< creasing increments in antibody level, rather than a thresh-
LOD = 1.59, 452) and 2360 (723, NC) BAU/ml, respectively old model where an antibody cut-point sharply discriminated
(NC = not calculated) (19). For COVE, there is low precision risk.
at 70% vaccine efficacy because few vaccine recipients had Together with evidence from other studies, the current re-
IgG < 100 BAU/ml, such that we only compare results at 90% sults support that neutralization titer is a potential surrogate
vaccine efficacy. Estimated mRNA-1273 vaccine efficacy was marker for mRNA-1273 vaccination against COVID-19 that
90% at Day 57 spike IgG level 298 (1, 1786) BAU/ml and at can be considered as a primary endpoint for basing certain
Day 57 RBD IgG level of 775 (29, 2819) BAU/ml. While the provisional approval decisions. For example, an immunogen-
point estimates of IgG levels at 90% efficacy were about 3 icity non-inferiority approach has been proposed for adding
times higher for COV002 than for COVE, the overlapping con- vaccine spike variants and boosters (34). An advantage of a
fidence intervals are consistent with similar results across the non-inferiority approach is avoiding the need to specify an
two trials. absolute antibody benchmark for approval, such as based on
Pseudovirus neutralization results can also be compared percentage of vaccine recipients with ID50 titer above a
between the trials using ID50 titers calibrated to the Interna- threshold and geometric mean titer above a threshold. Yet,
tional Standard, where estimated AZD1222 vaccine efficacy some applications may be aided by an absolute benchmark if
was 70% and 90% at ID50 titer of 8 (< LOD = 2.42, 26) and data allowing head-to-head non-inferiority evaluation are un-
140 (43, NC) IU50/ml, compared to COVE results at ID50 titer available. Such a benchmark based on ID50 values from vac-
of 4 (< LOD = 2.42, 22) and 83 (16, 188) IU50/ml. These results cinated individuals in a bridging study could be based on
support that neutralizing antibody titers have a similar quan- predicted vaccine efficacy being sufficiently high, where, for
titative relationship with vaccine efficacy for the two vaccine example, predicted vaccine efficacy could be calculated based
platforms, which is promising for potential applications of a on the COVE correlates of protection results (e.g., Fig. 4C) and
neutralization biomarker. The materials and methods pro- averaging over the distribution of ID50 values.
vide a sensitivity analysis comparing correlate of protection The evidence level for justifying various bridging applica-
results between COV002 and COVE. tions differs across applications, where currently confidence

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With the caveats of different study endpoints and hosts, is greatest for bridging short-term vaccine efficacy (i.e., over
the COVE results are also consistent with results on spike IgG 4-6 months) against COVID-19 to new subgroups for the same
and neutralizing antibody titers as correlates of protection vaccine (e.g., to young children), or for bridging to a modified
against SARS-CoV-2 replication in mRNA-1273-vaccinated dose or schedule for the same vaccine (e.g., completing the
rhesus macaques. For instance, all macaques with spike IgG primary series with a third dose). Less evidence is available
> 336 IU/ml at 4 weeks post second dose were protected from to buttress use of a humoral immune marker to predict long-
>10,000 subgenomic RNA copies/ml in bronchoalveolar lav- term protection, to bridge to a new vaccine within the same
ages (24), and in COVE, Day 57 spike IgG of 336 IU/ml corre- vaccine platform, or to bridge to new spike variant inserts for
sponded to 90% vaccine efficacy against COVID-19 (fig. S24). the same vaccine. An open question challenging the latter ap-
plication is whether higher neutralizing antibody responses
Concluding remarks to emergent SARS-CoV-2 variants such as delta will be
needed to achieve similar levels of vaccine efficacy, although
Our findings that all evaluated binding and neutralizing an-
modeling data are beginning to support the ability to make
tibody markers strongly inversely correlated with COVID-19
cross-variant predictions [e.g., (16)]. Less evidence still is
risk, and directly correlated with vaccine efficacy, adds evi-
available for justifying bridging to a new candidate vaccine
dence toward establishing an immune marker surrogate end-
in a different vaccine platform. When immune correlates re-
point for mRNA COVID-19 vaccines. Moreover, the pre-
sults are available from several COVID-19 phase 3 vaccine ef-
specification of the analyses and the absence of post-hoc
ficacy trials covering a multiplicity of vaccine platforms, it
modifications bolsters the credibility of our conclusions.
will be possible to conduct validation analyses of how well
For per-protocol recipients of two doses of mRNA-1273
antibody markers can be used to predict vaccine efficacy
COVID-19 vaccine in the COVE clinical trial, all four antibody
across platforms (35). Uncertainties in bridging predictions
markers at Day 29 and at Day 57 were inverse correlates of
can also be addressed by animal models that characterize im-
risk of COVID-19 occurrence through about 4 months post
munological mechanisms of vaccine protection and by post-
second dose. Based on any of the antibody markers, esti-
authorization/approval vaccine effectiveness studies [e.g.,
mated COVID-19 risk was about 10 times lower for vaccine
(36)]. Importantly, immune-marker based provisional ap-
recipients with antibodies in the top 10% of values compared
proval mechanisms require post-approval studies that verify
to those with negative/undetectable values. The nonparamet-
the vaccine provides direct clinical benefit, such that the
ric threshold analyses (e.g., Fig. 4A) suggested a continuum

First release: 23 November 2021 science.org (Page numbers not final at time of first release) 5
rigorous design and analysis of such studies is a critical com- Brosz, C. Fierro, H. Schwartz, K. Neuzil, L. Corey, P. Gilbert, H. Janes, D. Follmann,
M. Marovich, J. Mascola, L. Polakowski, J. Ledgerwood, B. S. Graham, H. Bennett,
ponent of the decision-making process for use of immune
R. Pajon, C. Knightly, B. Leav, W. Deng, H. Zhou, S. Han, M. Ivarsson, J. Miller, T.
markers to accelerate approval and distribution of vaccines. Zaks; COVE Study Group, Efficacy and Safety of the mRNA-1273 SARS-CoV-2
Limitations of this immune correlates study include the Vaccine. N. Engl. J. Med. 384, 403–416 (2021). doi:10.1056/NEJMoa2035389
inability to control for SARS-CoV-2 exposure factors (e.g., vi- Medline
7. US Food and Drug Administration, “Moderna COVID-19 Vaccine,” (updated 1 April
rus magnitude) and lack of experimental assignment of anti-
2021); www.fda.gov/emergency-preparedness-and-response/coronavirus-
body levels, implying the study could evaluate statistical disease-2019-covid-19/moderna-covid-19-vaccine.
correlates of protection/surrogate endpoints but not mecha- 8. M. G. Thompson, J. L. Burgess, A. L. Naleway, H. L. Tyner, S. K. Yoon, J. Meece, L. E.
nistic correlates of protection (10). In addition, scope limita- W. Olsho, A. J. Caban-Martinez, A. Fowlkes, K. Lutrick, J. L. Kuntz, K. Dunnigan, M.
J. Odean, K. T. Hegmann, E. Stefanski, L. J. Edwards, N. Schaefer-Solle, L. Grant,
tions include 1) the lack of data for assessing correlates
K. Ellingson, H. C. Groom, T. Zunie, M. S. Thiese, L. Ivacic, M. G. Wesley, J. M.
against other outcomes besides COVID-19 (e.g., severe Lamberte, X. Sun, M. E. Smith, A. L. Phillips, K. D. Groover, Y. M. Yoo, J. Gerald, R.
COVID-19, asymptomatic SARS-CoV-2 infection, infection re- T. Brown, M. K. Herring, G. Joseph, S. Beitel, T. C. Morrill, J. Mak, P. Rivers, K. M.
gardless of symptomology, viral shedding); 2) the lack of as- Harris, D. R. Hunt, M. L. Arvay, P. Kutty, A. M. Fry, M. Gaglani, Interim Estimates of
Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in
sessment of non-antibody based correlates (e.g., spike-
Preventing SARS-CoV-2 Infection Among Health Care Personnel, First
specific functional T-cell responses, which were not feasible Responders, and Other Essential and Frontline Workers - Eight U.S. Locations,
to assess in the context of this study); 3) the relatively short December 2020-March 2021. MMWR Morb. Mortal. Wkly. Rep. 70, 495–500
follow-up time of 4 months that precluded assessment of im- (2021). doi:10.15585/mmwr.mm7013e3 Medline
9. Moderna, “Moderna Announces TeenCOVE Study of its COVID-19 Vaccine in
mune correlate durability; 4) the relatively small number of
Adolescents Meets Primary Endpoint and Plans to Submit Data to Regulators in
COVID-19 cases; 5) the lack of assessment of correlates for Early June” (press release, 25 May 2021);
recipients of only one mRNA-1273 dose; 6) the inability to as- https://investors.modernatx.com/news-releases/news-release-
sess the effects of boosting (homologous or heterologous) as details/moderna-announces-teencove-study-its-covid-19-vaccine.
10. S. A. Plotkin, P. B. Gilbert, Nomenclature for immune correlates of protection after
this study pre-dated the addition of a third dose; 7) the lack
vaccination. Clin. Infect. Dis. 54, 1615–1617 (2012). doi:10.1093/cid/cis238
of data for assessing the potential contribution of anamnestic Medline
responses to the immune correlates; and 8) the fact that al- 11. S. A. Plotkin, Correlates of protection induced by vaccination. Clin. Vaccine
most all COVID-19 cases resulted from infections with viruses Immunol. 17, 1055–1065 (2010). doi:10.1128/CVI.00131-10 Medline

Downloaded from https://www.science.org on December 02, 2021


12. S. A. Plotkin, P. B. Gilbert, in Plotkin’s Vaccines, S. A. Plotkin, W. A. Orenstein, P. A.
with spike sequences similar to that of the vaccine strain, pre-
Offit, K. M. Edwards, Eds. (Elsevier, seventh ed., 2018), chap. 3.
cluding assessment of robustness of correlates to SARS-CoV- 13. J. Yu, L. H. Tostanoski, L. Peter, N. B. Mercado, K. McMahan, S. H. Mahrokhian, J.
2 variants of concern. However, the relative uniformity in cir- P. Nkolola, J. Liu, Z. Li, A. Chandrashekar, D. R. Martinez, C. Loos, C. Atyeo, S.
culating virus is also a strength in affording a clear interpre- Fischinger, J. S. Burke, M. D. Slein, Y. Chen, A. Zuiani, F. J. N. Lelis, M. Travers, S.
tation as correlates against COVID-19 caused by variants Habibi, L. Pessaint, A. Van Ry, K. Blade, R. Brown, A. Cook, B. Finneyfrock, A.
Dodson, E. Teow, J. Velasco, R. Zahn, F. Wegmann, E. A. Bondzie, G. Dagotto, M.
genetically close to the vaccine. An additional strength is the S. Gebre, X. He, C. Jacob-Dolan, M. Kirilova, N. Kordana, Z. Lin, L. F. Maxfield, F.
racial and ethnic diversity of the trial participants and large Nampanya, R. Nityanandam, J. D. Ventura, H. Wan, Y. Cai, B. Chen, A. G. Schmidt,
number of diverse participants sampled for immunogenicity D. R. Wesemann, R. S. Baric, G. Alter, H. Andersen, M. G. Lewis, D. H. Barouch,
measurements (37). DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 369,
806–811 (2020). doi:10.1126/science.abc6284 Medline
REFERENCES AND NOTES 14. X. He, A. Chandrashekar, R. Zahn, F. Wegmann, J. Yu, N. B. Mercado, K. McMahan,
A. J. Martinot, C. Piedra-Mora, S. Beecy, S. Ducat, R. Chamanza, S. R. Huber, M.
1. World Health Organization, “Coronavirus Disease (COVID-19): COVID-19 vaccine van Heerden, L. van der Fits, E. N. Borducchi, M. Lifton, J. Liu, F. Nampanya, S.
EUL issued” (2021); https://extranet.who.int/pqweb/vaccines/covid-19- Patel, L. Peter, L. H. Tostanoski, L. Pessaint, A. Van Ry, B. Finneyfrock, J. Velasco,
vaccines. E. Teow, R. Brown, A. Cook, H. Andersen, M. G. Lewis, H. Schuitemaker, D. H.
2. US Food and Drug Administration (FDA), “COVID-19 Vaccines: COVID-19 Vaccines Barouch, Low-dose Ad26.COV2.S protection against SARS-CoV-2 challenge in
Authorized for Emergency Use” (2021); www.fda.gov/emergency-preparedness- rhesus macaques. Cell 184, 3467–3473.e11 (2021).
and-response/coronavirus-disease-2019-covid-19/covid-19-vaccines#news doi:10.1016/j.cell.2021.05.040 Medline
[last updated 11 March 2021]. 15. K. McMahan, J. Yu, N. B. Mercado, C. Loos, L. H. Tostanoski, A. Chandrashekar, J.
3. US Food and Drug Administration, “FDA Approves First COVID-19 Vaccine: Approval Liu, L. Peter, C. Atyeo, A. Zhu, E. A. Bondzie, G. Dagotto, M. S. Gebre, C. Jacob-
Signifies Key Achievement for Public Health” (FDA news release, 23 August 2021); Dolan, Z. Li, F. Nampanya, S. Patel, L. Pessaint, A. Van Ry, K. Blade, J. Yalley-
www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19- Ogunro, M. Cabus, R. Brown, A. Cook, E. Teow, H. Andersen, M. G. Lewis, D. A.
vaccine. Lauffenburger, G. Alter, D. H. Barouch, Correlates of protection against SARS-
4. C. Weller, “Four reasons why we need multiple vaccines for Covid-19” (Wellcome CoV-2 in rhesus macaques. Nature 590, 630–634 (2021). doi:10.1038/s41586-
Opinion, 6 June 2021); https://wellcome.org/news/four-reasons-why-we-need- 020-03041-6 Medline
multiple-vaccines-covid-19. 16. D. S. Khoury, D. Cromer, A. Reynaldi, T. E. Schlub, A. K. Wheatley, J. A. Juno, K.
5. O. J. Wouters, K. C. Shadlen, M. Salcher-Konrad, A. J. Pollard, H. J. Larson, Y. Subbarao, S. J. Kent, J. A. Triccas, M. P. Davenport, Neutralizing antibody levels
Teerawattananon, M. Jit, Challenges in ensuring global access to COVID-19 are highly predictive of immune protection from symptomatic SARS-CoV-2
vaccines: Production, affordability, allocation, and deployment. Lancet 397, infection. Nat. Med. 27, 1205–1211 (2021). doi:10.1038/s41591-021-01377-8
1023–1034 (2021). doi:10.1016/S0140-6736(21)00306-8 Medline Medline
6. L. R. Baden, H. M. El Sahly, B. Essink, K. Kotloff, S. Frey, R. Novak, D. Diemert, S. A. 17. K. A. Earle, D. M. Ambrosino, A. Fiore-Gartland, D. Goldblatt, P. B. Gilbert, G. R.
Spector, N. Rouphael, C. B. Creech, J. McGettigan, S. Khetan, N. Segall, J. Solis, A. Siber, P. Dull, S. A. Plotkin, Evidence for antibody as a protective correlate for

First release: 23 November 2021 science.org (Page numbers not final at time of first release) 6
COVID-19 vaccines. Vaccine 39, 4423–4428 (2021). 29. T. J. VanderWeele, P. Ding, Sensitivity Analysis in Observational Research:
doi:10.1016/j.vaccine.2021.05.063 Medline Introducing the E-Value. Ann. Intern. Med. 167, 268–274 (2017).
18. D. Cromer, A. Reynaldi, M. Steain, J. A. Triccas, M. P. Davenport, D. S. Khoury, doi:10.7326/M16-2607 Medline
Relating in vitro neutralisation level and protection in the CVnCoV (CUREVAC) 30. D. Benkeser, I. Díaz, J. Ran, Inference for natural mediation effects under case-
trial. medRxiv 2021.06.29.21259504 [Preprint] (2021). cohort sampling with applications in identifying COVID-19 vaccine correlates of
https://doi.org/10.1101/2021.06.29.21259504. protection. arXiv:2103.02643 [stat.ME] (2021).
19. S. Feng, D. J. Phillips, T. White, H. Sayal, P. K. Aley, S. Bibi, C. Dold, M. Fuskova, S. 31. B. J. Cowling, W. W. Lim, R. A. P. M. Perera, V. J. Fang, G. M. Leung, J. S. M. Peiris,
C. Gilbert, I. Hirsch, H. E. Humphries, B. Jepson, E. J. Kelly, E. Plested, K. E. J. Tchetgen Tchetgen, Influenza Hemagglutination-inhibition Antibody Titer as
Shoemaker, K. M. Thomas, J. Vekemans, T. L. Villafana, T. Lambe, A. J. Pollard, M. a Mediator of Vaccine-induced Protection for Influenza B. Clin. Infect. Dis. 68,
Voysey, Oxford COVID Vaccine Trial Group, Correlates of protection against 1713–1717 (2019). doi:10.1093/cid/ciy759 Medline
symptomatic and asymptomatic SARS-CoV-2 infection. medRxiv 32. T. R. Fleming, J. H. Powers, Biomarkers and surrogate endpoints in clinical trials.
2021.06.21.21258528 [Preprint] (2021). Stat. Med. 31, 2973–2984 (2012). doi:10.1002/sim.5403 Medline
https://doi.org/10.1101/2021.06.21.21258528. 33. M. Voysey, S. A. C. Clemens, S. A. Madhi, L. Y. Weckx, P. M. Folegatti, P. K. Aley, B.
20. A. Addetia, K. H. D. Crawford, A. Dingens, H. Zhu, P. Roychoudhury, M. L. Huang, Angus, V. L. Baillie, S. L. Barnabas, Q. E. Bhorat, S. Bibi, C. Briner, P. Cicconi, A. M.
K. R. Jerome, J. D. Bloom, A. L. Greninger, Neutralizing Antibodies Correlate with Collins, R. Colin-Jones, C. L. Cutland, T. C. Darton, K. Dheda, C. J. A. Duncan, K. R.
Protection from SARS-CoV-2 in Humans during a Fishery Vessel Outbreak with a W. Emary, K. J. Ewer, L. Fairlie, S. N. Faust, S. Feng, D. M. Ferreira, A. Finn, A. L.
High Attack Rate. J. Clin. Microbiol. 58, e02107-20 (2020). Goodman, C. M. Green, C. A. Green, P. T. Heath, C. Hill, H. Hill, I. Hirsch, S. H. C.
doi:10.1128/JCM.02107-20 Medline Hodgson, A. Izu, S. Jackson, D. Jenkin, C. C. D. Joe, S. Kerridge, A. Koen, G. Kwatra,
21. S. S. Abdool Karim, T. de Oliveira, New SARS-CoV-2 Variants - Clinical, Public R. Lazarus, A. M. Lawrie, A. Lelliott, V. Libri, P. J. Lillie, R. Mallory, A. V. A. Mendes,
Health, and Vaccine Implications. N. Engl. J. Med. 384, 1866–1868 (2021). E. P. Milan, A. M. Minassian, A. McGregor, H. Morrison, Y. F. Mujadidi, A. Nana, P.
doi:10.1056/NEJMc2100362 Medline J. O’Reilly, S. D. Padayachee, A. Pittella, E. Plested, K. M. Pollock, M. N. Ramasamy,
22. M. S. Cohen, A. Nirula, M. J. Mulligan, R. M. Novak, M. Marovich, C. Yen, A. Stemer, S. Rhead, A. V. Schwarzbold, N. Singh, A. Smith, R. Song, M. D. Snape, E. Sprinz,
S. M. Mayer, D. Wohl, B. Brengle, B. T. Montague, I. Frank, R. J. McCulloh, C. J. R. K. Sutherland, R. Tarrant, E. C. Thomson, M. E. Török, M. Toshner, D. P. J.
Fichtenbaum, B. Lipson, N. Gabra, J. A. Ramirez, C. Thai, W. Chege, M. M. Gomez Turner, J. Vekemans, T. L. Villafana, M. E. E. Watson, C. J. Williams, A. D. Douglas,
Lorenzo, N. Sista, J. Farrior, M. E. Clement, E. R. Brown, K. L. Custer, J. Van A. V. S. Hill, T. Lambe, S. C. Gilbert, A. J. Pollard; Oxford COVID Vaccine Trial
Naarden, A. C. Adams, A. E. Schade, M. C. Dabora, J. Knorr, K. L. Price, J. Sabo, J. Group, Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against
L. Tuttle, P. Klekotka, L. Shen, D. M. Skovronsky; BLAZE-2 Investigators, Effect of SARS-CoV-2: An interim analysis of four randomised controlled trials in Brazil,
Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff South Africa, and the UK. Lancet 397, 99–111 (2021). doi:10.1016/S0140-
of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial. JAMA 6736(20)32661-1 Medline
326, 46–55 (2021). doi:10.1001/jama.2021.8828 Medline 34. US Department of Health and Human Services, Food and Drug Administration,
23. Regeneron, “Phase 3 Prevention Trial Showed 81% Reduced Risk of Symptomatic Center for Biologics Evaluation and Research, “Emergency Use Authorization for

Downloaded from https://www.science.org on December 02, 2021


SARS-CoV-2 Infections with Subcutaneous Administration of REGEN-COV™ Vaccines to Prevent COVID-19: Guidance for Industry,” appendix 2, pp. 18–22 (25
(casirivimab with imdevimab)” (press release, 12 April 2021); May 2021); www.fda.gov/regulatory-information/search-fda-guidance-
https://investor.regeneron.com/news-releases/news-release-details/phase-3- documents/emergency-use-authorization-vaccines-prevent-covid-19.
prevention-trial-showed-81-reduced-risk-symptomatic-sars. 35. R. A. Koup, R. O. Donis, P. B. Gilbert, A. W. Li, N. A. Shah, C. R. Houchens, A
24. K. S. Corbett, M. C. Nason, B. Flach, M. Gagne, S. O’Connell, T. S. Johnston, S. N. government-led effort to identify correlates of protection for COVID-19 vaccines.
Shah, V. V. Edara, K. Floyd, L. Lai, C. McDanal, J. R. Francica, B. Flynn, K. Wu, A. Nat. Med. 27, 1493–1494 (2021). doi:10.1038/s41591-021-01484-6 Medline
Choi, M. Koch, O. M. Abiona, A. P. Werner, J. I. Moliva, S. F. Andrew, M. M. 36. J. Kertes, S. B. Gez, Y. Saciuk, L. Supino-Rosin, N. S. Stein, M. Mizrahi-Reuveni, A.
Donaldson, J. Fintzi, D. R. Flebbe, E. Lamb, A. T. Noe, S. T. Nurmukhambetova, S. E. Zohar, Effectiveness of the mRNA BNT162b2 vaccine six months after
J. Provost, A. Cook, A. Dodson, A. Faudree, J. Greenhouse, S. Kar, L. Pessaint, M. vaccination: findings from a large Israeli HMO. medRxiv 2021.09.01.21262957
Porto, K. Steingrebe, D. Valentin, S. Zouantcha, K. W. Bock, M. Minai, B. M. Nagata, [Preprint] (2021). https://doi.org/10.1101/2021.09.01.21262957.
R. van de Wetering, S. Boyoglu-Barnum, K. Leung, W. Shi, E. S. Yang, Y. Zhang, J. 37. M. P. Andrasik, G. B. Broder, S. E. Wallace, R. Chaturvedi, N. L. Michael, S. Bock, C.
M. Todd, L. Wang, G. S. Alvarado, H. Andersen, K. E. Foulds, D. K. Edwards, J. R. Beyrer, L. Oseso, J. Aina, J. Lucas, D. R. Wilson, J. G. Kublin, G. A. Mensah,
Mascola, I. N. Moore, M. G. Lewis, A. Carfi, D. Montefiori, M. S. Suthar, A. Increasing Black, Indigenous and People of Color participation in clinical trials
McDermott, M. Roederer, N. J. Sullivan, D. C. Douek, B. S. Graham, R. A. Seder, through community engagement and recruitment goal establishment. PLOS ONE
Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in 16, e0258858 (2021). doi:10.1371/journal.pone.0258858 Medline
nonhuman primates. Science 373, eabj0299 (2021). 38. P. B. Gilbert, Y. Fong, D. Benkeser, N. S. Hejazi, E. Hughes, B. R. Borate, C. Yu, Y.
doi:10.1126/science.abj0299 Medline Lu, K. Q. Li, L. W. P. van der Laan, B. Simpkins, COVID-19 Prevention Network
25. M. Bergwerk, T. Gonen, Y. Lustig, S. Amit, M. Lipsitch, C. Cohen, M. Mandelboim, Immune Correlates Analyses, version 1.1.1, Zenodo (2021);
E. G. Levin, C. Rubin, V. Indenbaum, I. Tal, M. Zavitan, N. Zuckerman, A. Bar- https://doi.org/10.5281/zenodo.5593130.
Chaim, Y. Kreiss, G. Regev-Yochay, Covid-19 Breakthrough Infections in 39. X. Shen, H. Tang, C. McDanal, K. Wagh, W. Fischer, J. Theiler, H. Yoon, D. Li, B. F.
Vaccinated Health Care Workers. N. Engl. J. Med. 385, 1474–1484 (2021). Haynes, K. O. Sanders, S. Gnanakaran, N. Hengartner, R. Pajon, G. Smith, G. M.
doi:10.1056/NEJMoa2109072 Medline Glenn, B. Korber, D. C. Montefiori, SARS-CoV-2 variant B.1.1.7 is susceptible to
26. P. R. Krause, T. R. Fleming, R. Peto, I. M. Longini, J. P. Figueroa, J. A. C. Sterne, A. neutralizing antibodies elicited by ancestral spike vaccines. Cell Host Microbe 29,
Cravioto, H. Rees, J. P. T. Higgins, I. Boutron, H. Pan, M. F. Gruber, N. Arora, F. 529–539.e3 (2021). doi:10.1016/j.chom.2021.03.002 Medline
Kazi, R. Gaspar, S. Swaminathan, M. J. Ryan, A.-M. Henao-Restrepo, 40. P. A. Kristiansen, M. Page, V. Bernasconi, G. Mattiuzzo, P. Dull, K. Makar, S. Plotkin,
Considerations in boosting COVID-19 vaccine immune responses. Lancet 398, I. Knezevic, WHO International Standard for anti-SARS-CoV-2 immunoglobulin.
1377–1380 (2021). doi:10.1016/S0140-6736(21)02046-8 Medline Lancet 397, 1347–1348 (2021). doi:10.1016/S0140-6736(21)00527-4 Medline
27. G. R. Siber, I. Chang, S. Baker, P. Fernsten, K. L. O’Brien, M. Santosham, K. P. 41. National Institute for Biological Standards and Control (NIBSC), “Instructions for
Klugman, S. A. Madhi, P. Paradiso, R. Kohberger, Estimating the protective use of First WHO International Standard for anti-SARS-CoV-2 Immunoglobulin”
concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine (NIBSC code: 20/136, version 3.0, 17 December 2020);
25, 3816–3826 (2007). doi:10.1016/j.vaccine.2007.01.119 Medline www.nibsc.org/science_and_research/idd/cfar/covid-19_reagents.aspx.
28. P. B. Gilbert, Y. Fong, M. Carone, Assessment of Immune Correlates of Protection 42. R. L. Prentice, A Case-Cohort Design for Epidemiologic Cohort Studies and
via Controlled Vaccine Efficacy and Controlled Risk. arXiv:2107.05734 [stat.ME] Disease Prevention Trials. Biometrika 73, 1–11 (1986). doi:10.1093/biomet/73.1.1
(2021). 43. R. G. Newcombe, Two-sided confidence intervals for the single proportion:

First release: 23 November 2021 science.org (Page numbers not final at time of first release) 7
Comparison of seven methods. Stat. Med. 17, 857–872 (1998). support (in the form of payments to their institution) from Moderna for the
doi:10.1002/(SICI)1097-0258(19980430)17:8<857:AID-SIM777>3.0.CO;2-E submitted work; WD, HZ, JM, and RP are employed by Moderna Tx, Inc. and have
Medline stock and/or stock options in Moderna Tx, Inc.; LRB declares support (in the
44. T. Lumley, Complex Surveys: A Guide to Analysis Using R, vol. 565 (Wiley, 2010). form of grant payments to his institution) within the previous three years from
45. S. N. Wood, Generalized Additive Models: An Introduction with R (CRC Press, 2017). the National Institutes of Health, the Wellcome Trust, and the Bill and Melinda
46. L. van der Laan, W. Zhang, P. B. Gilbert, Efficient nonparametric estimation of the Gates Foundation and has served on NIAID-NIH SMCs within the previous three
covariate-adjusted threshold-response function, a support-restricted stochastic years; MB declares support (in the form of grant payments to her institution)
intervention. arXiv:2107.11459 [stat.ME] (2021). within the previous three years from the National Institutes of Health and the
47. P. H. Westfall, S. S. Young, Resampling-Based Multiple Testing: Examples and Centers for Disease Control; CFK declares support (in the form of grant
Methods for P-Value Adjustment, vol. 279 of Wiley Series in Probability and payments to her institution) within the previous three years from the National
Statistics (Wiley, 1993). Institutes of Health, the Centers for Disease Control, Humanigen, Novavax, Viiv,
48. B. D. Williamson, P. B. Gilbert, N. R. Simon, M. Carone, A general framework for and Gilead, as well as payments from Medscape and from Clinical Care Options
inference on algorithm-agnostic variable importance. arXiv:2004.03683 within the previous three years for educational events; KMN declares support (in
[stat.ME] (2020). the form of grant payments to her institution) within the previous three years
49. A. E. Hubbard, S. Kherad-Pajouh, M. J. van der Laan, Statistical Inference for Data from GSK, Pfizer, Bill & Melinda Gates Foundation, and PATH for vaccine
Adaptive Target Parameters. Int. J. Biostat. 12, 3–19 (2016). doi:10.1515/ijb-2015- research, as well as support (in the form of grant payments to her institution)
0013 Medline within the previous three years from the National Institutes of Health for
50. S. D. Neidich, Y. Fong, S. S. Li, D. E. Geraghty, B. D. Williamson, W. C. Young, D. influenza vaccine research; and DCM declares support from Moderna within the
Goodman, K. E. Seaton, X. Shen, S. Sawant, L. Zhang, A. C. deCamp, B. S. Blette, previous three years for work outside the scope of the submitted work. All other
M. Shao, N. L. Yates, F. Feely, C.-W. Pyo, G. Ferrari, HVTN 505 Team, I. Frank, S. authors declare no support from any organization for the submitted work; no
T. Karuna, E. M. Swann, J. R. Mascola, B. S. Graham, S. M. Hammer, M. E. financial relationships with any organizations that might have an interest in the
Sobieszczyk, L. Corey, H. E. Janes, M. J. McElrath, R. Gottardo, P. B. Gilbert, G. D. submitted work in the previous three years, and no other relationships or
Tomaras, Antibody Fc effector functions and IgG3 associate with decreased HIV- activities that could appear to have influenced the submitted work. Data and
1 risk. J. Clin. Invest. 129, 4838–4849 (2019). doi:10.1172/JCI126391 Medline materials availability: As the trial is ongoing, access to participant-level data
51. C. A. Magaret, D. C. Benkeser, B. D. Williamson, B. R. Borate, L. N. Carpp, I. S. and supporting clinical documents with qualified external researchers may be
Georgiev, I. Setliff, A. S. Dingens, N. Simon, M. Carone, C. Simpkins, D. Montefiori, available upon request and subject to review once the trial is complete. The code
G. Alter, W. H. Yu, M. Juraska, P. T. Edlefsen, S. Karuna, N. M. Mgodi, S. is publicly available at Zenodo (38). This work is licensed under a Creative
Edugupanti, P. B. Gilbert, Prediction of VRC01 neutralization sensitivity by HIV-1 Commons Attribution 4.0 International (CC BY 4.0) license, which permits
gp160 sequence features. PLOS Comput. Biol. 15, e1006952 (2019). unrestricted use, distribution, and reproduction in any medium, provided the
doi:10.1371/journal.pcbi.1006952 Medline original work is properly cited. To view a copy of this license, visit
52. B. D. Williamson, J. Feng, N. Simon, M. Carone, vimp: Perform Inference on https://creativecommons.org/licenses/by/4.0/. This license does not apply to

Downloaded from https://www.science.org on December 02, 2021


Algorithm-Agnostic Variable Importance, version 2.2.2 (2021); https://cran.r- figures/photos/artwork or other content included in the article that is credited
project.org/web/packages/vimp/index.html. to a third party; obtain authorization from the rights holder before using such
53. P. Ding, T. J. VanderWeele, Sensitivity Analysis Without Assumptions. material.
Epidemiology 27, 368–377 (2016). doi:10.1097/EDE.0000000000000457
Medline SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abm3425
ACKNOWLEDGMENTS Materials and Methods
Supplementary Text
We thank the volunteers who participated in the COVE trial. We also thank J. Figs. S1 to S30
Mascola, M. Hepburn, R. A. Johnson, M. Marovich, and M. Robb. Funding: Public Tables S1 to S9
Health Service, National Institute of Allergy and Infectious Diseases, National Immune Assays Team Collaborator List
Institutes of Health grant UM1AI068635 (PBG). Office of Research Infrastructure Moderna, Inc. Team Collaborator List
Programs (ORIP), National Institutes of Health grant (S10OD028685) (Fred CoVPN/COVE Team Collaborator List
Hutchinson Cancer Research Center). Moderna, Inc. Federal funds from the USG/CoVPN Biostatistics Team Collaborator List
Office of the Assistant Secretary for Preparedness and Response, Biomedical References (39–53)
Advanced Research and Development Authority, Contract No. MDAR Reproducibility Checklist
75A50120C00034 (Moderna, Inc.). Infectious Disease Clinical Research Statistical Analysis Plan
Consortium (IDCRC) Leadership Group through the National Institute for Allergy
and Infectious Diseases, grant UM1 AI148684-03 (KMN). Author contributions: 16 September 2021; accepted 16 November 2021
Conceptualization: PBG, DCM, ABM, YF, DB, DF, ROD, RAK. Data curation: PBG, Published online 23 November 2021
YF, DB, WD, HZ, YL, CY, BB, LvdL, NH. Formal analysis: PBG, YF, DB, YL, CY, BB, 10.1126/science.abm3425
LvdL, NH. Funding acquisition: PBG, ROD, RAK. Investigation: DCM, ABM, KM,
LJ, FC, BF, BCL, SOC, CM, AE, MS-K. Methodology: PBG, YF, DB, LvdL, DF.
Project administration: CRH, SOC, MS-K, CH, ROD, RAK. Resources: DCM, ABM,
JM, HMES, LRB, BM, LDLC, CG, SK, CFK, MPA, JGK, LC, KMN, RP, ROD, RAK.
Software: PBG, YF, DB, YL, CY, BB, LvdL, NH. Supervision: PBG, DCM, ABM, YF,
DB, DF, ROD, RAK. Validation: PBG, YF, DB. Visualization: PBG, YF, DB, YL, BB,
LvdL, LNC. Writing – original draft: PBG, LNC. Writing – review and editing: All
co-authors. Competing interests: All authors have completed the ICMJE
uniform disclosure form at www.icmje.org/downloads/coi_disclosure.docx and
declare: PBG, DCM, YF, CM, AE, MS-K, YL, CY, BB, LvdL, HMES, LRB, MB, CFK,
MPA, LC, and LNC had support (in the form of grant payments to their
institution) from the National Institutes of Health for the submitted work; RAK
had support (in the form of funds to the VRC to cover assay performance) from
the National Institutes of Health for the submitted work; MB, LDLC, and CFK had

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Fig. 1. (A) Anti-spike IgG concentration and (B) pseudovirus neutralization ID50 titer by COVID-19 outcome
status. Data points are from baseline negative per-protocol vaccine recipients in the Day 29 marker or Day 57
marker case-cohort set. The violin plots contain interior box plots with upper and lower horizontal edges the 25th
and 75th percentiles of antibody level and middle line the 50th percentile, and vertical bars the distance from the
25th (or 75th) percentile of antibody level and the minimum (or maximum) antibody level within the 25th (or 75th)
percentile of antibody level minus (or plus) 1.5 times the interquartile range. Each side shows a rotated
probability density (estimated by a kernel density estimator with a default Gaussian kernel) of the data. Positive
response rates were computed with inverse probability of sampling weighting. Pos.Cut, Positivity cut-off. LoD,
limit of detection. ULoQ, upper limit of quantitation; ULOQ = 10,919 for ID50 (above all data points). Positive
response for spike IgG was defined by IgG > 10.8424 BAU/ml. Positive response for ID50 was defined by value
> LoD (2.42). Post Day 57 cases are COVID-19 endpoints starting 7 days post Day 57 through the end of blinded
follow-up (last COVID-19 endpoint 126 days post dose 2); Intercurrent cases are COVID-19 endpoints starting 7
days post Day 29 through 6 days post Day 57.

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Fig. 2. COVID-19 risk by antibody marker level. The plots and table show covariate-adjusted cumulative
incidence of COVID-19 by Low, Medium, High tertile of Day 57 IgG concentration or pseudovirus
neutralization titer in baseline SARS-CoV-2 negative per-protocol participants. (A) Anti-spike IgG
concentration; (B) ID50 titer; (C) IgG (spike, RBD) and (ID50, ID80). The overall p-value is from a
generalized Wald test of whether the hazard rate of COVID-19 differed across the Low, Medium, and High
subgroups. Baseline covariates adjusted for: baseline risk score, at risk status, community of color status.

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Fig. 3. Hazard ratio of COVID-19 as antibody marker level increases. The table and plots show
covariate-adjusted hazard ratios of COVID-19 per 10-fold increase in each Day 57 antibody marker
in baseline negative per-protocol vaccine recipients overall and in subgroups. (A) Inferences for
IgG (spike, RBD) and (ID50, ID80); (B) Forest plots for spike IgG; (C) Forest plots for ID50.
Baseline covariates adjusted for: baseline risk score, at risk status, community of color status.

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Fig. 4. Further analyses of Day 57 ID50 level as a correlate of risk and as a correlate of protection. (A)
Covariate-adjusted cumulative incidence of COVID-19 by 100 days post Day 57 by vaccinated baseline SARS-
CoV-2 negative per-protocol subgroups defined by Day 57 ID50 level above a threshold, with reverse cumulative
distribution function (CDF) of Day 57 ID50 level overlaid in green. The red dots are point estimates at 35
threshold values equally spaced over quantiles of the observed marker values, linearly interpolated by solid black
lines; the gray shaded area is pointwise 95% confidence intervals (CIs). The upper boundary of the green shaded
area is the estimate of the reverse cumulative distribution function (CDF) of Day 57 ID50 level in baseline SARS-
CoV-2 negative per-protocol vaccine recipients. The vertical red dashed line is the Day 57 ID50 threshold above
which no post Day 57 COVID endpoints occurred. (B) Covariate-adjusted cumulative incidence of COVID-19 by
100 days post Day 57 by Day 57 ID50 level. The dotted black lines indicate bootstrap point-wise 95% CIs. The
upper and lower horizontal gray lines are the overall cumulative incidence of COVID-19 from 7 to 100 days post
Day 57 in placebo and vaccine recipients, respectively. (C) Vaccine efficacy (solid black line) by Day 57 ID50
level, estimated using the method of Gilbert, Fong, and Carone (28). The dashed black lines indicate bootstrap
point-wise 95% CIs. The horizontal gray line is the overall vaccine efficacy from 7 to 100 days post Day 57, with
the dotted gray lines indicating the 95% CIs (this number 92.8% differs from the 94.1% reported in (6), which
was based on counting COVID-19 endpoints starting 14 days post Day 29). In (B) and (C), the green histograms
are an estimate of the density of Day 57 ID50 level in baseline negative per-protocol vaccine recipients. LOD, limit
of detection. Baseline covariates adjusted for: baseline risk score, at risk status, community of color status.

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Table 1. Anti-spike and anti-RBD IgG response rates and Geometric Mean Concentrations (GMCs) and pseudovirus calibrated neutraliza-
tion titer ID50 and ID80 response rates and Geometric Mean Titers (GMTs) by COVID-19 outcome status. Analysis based on baseline nega-
tive per-protocol vaccine recipients in the Day 29 marker or Day 57 marker case-cohort sets. Median (interquartile range) days from dose one to
Day 29 was 28 (28 to 30) and from Day 29 to Day 57 was 28 (28 to 30).

COVID-19 Cases* Non-Cases in Immunogenicity Subcohort Comparison


Visit Marker N Response Rate GMC or N Response Rate GMC or GMT Response Ratio of GM
for (95% CI) GMT (95% (95% CI) (95% CI) Rate Differ- (Cases/Non
Marker CI) ence (95% -Cases)
CI) (95% CI)
Day 29 Anti spike IgG 46 97.8% 183 1005 98.6% 318 -1% 0.57
(BAU/ml) (85.4%, 99.7%) (126, 266) (97.4%, 99.2%) (292, 347) (-13, 1%) (0.39, 0.84)
Day 29 Anti RBD IgG 46 97.8% 207 1005 98.4% 327 -1% 0.63
(BAU/ml) (85.4%, 99.7%) (147, 293) (97.2%, 99.1%) (302, 354) (-13, 2%) (0.44, 0.90)

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Day 29 Pseudovirus-nAb 46 65.2% 7.6 1005 81.7% 13.0 -17% 0.59
ID50 (IU50/ml) (50.1%, 77.8%) (5.4, 10.8) (78.8%, 84.3%) (11.9, 14.1) (-32, -4%) (0.41, 0.84)
Day 29 Pseudovirus-nAb 46 43.5% 18.0 1005 63.9% 29.0 -20% 0.62
ID80 (IU80/ml) (29.7%, 58.4%) (13.3, 24.2) (60.4%, 67.3%) (27.1, 31.0) (-35, -5%) (0.46, 0.84)
Day 57 Anti spike IgG 36 100.0% 1890 1005 99.4% 2652 1% 0.71
(BAU/ml) (100.0%, (1449, 2465) (98.2%, 99.8%) (2457, 2863) (0, 2%) (0.54, 0.94)
100.0%)
Day 57 Anti RBD IgG 36 100.0% 2744 1005 99.4% 3937 1% 0.70
(BAU/ml) (100.0%, (2056, (98.3%, 99.8%) (3668, 4227) (0%, 2%) (0.52, 0.94)
100.0%) 3664)
Day 57 Pseudovirus-nAb 36 100.0% 160 1005 98.7% 247 1% 0.65
ID50 (IU50/ml) (100.0%, (117, 220) (97.6%, 99.3%) (231, 264) (1, 2%) (0.47, 0.90)
100.0%)
Day 57 Pseudovirus-nAb 36 97.2% 332 1005 98.3% 478 -1% 0.69
ID80 (IU80/ml) (81.6%, 99.6%) (248, 444) (97.1%, 99.1%) (450, 508) (-17, 2%) (0.52, 0.93)
*Cases for Day 29 marker correlates analyses (Intercurrent cases + Post Day 57 cases) are baseline SARS-CoV-2 negative per-protocol vaccine
recipients with the symptomatic infection COVID-19 primary endpoint diagnosed starting 7 days after Day 29 through the end of the blinded
phase. Cases for Day 57 marker correlates analyses (Post Day 57 cases) are baseline SARS-CoV-2 negative per-protocol vaccine recipients with
the symptomatic infection COVID-19 primary endpoint diagnosed starting 7 days after Day 57 through the end of the blinded phase. The last
COVID-19 endpoint within the blinded phase occurred 100 days after Day 57.
N for Non-Cases in Immunogenicity Subcohort is the number of participants with Day 1, 29, 57 antibody marker data included in both the Day 29
and Day 57 marker correlates analyses. N for Cases for Day 29 marker analyses is the number of vaccine breakthrough cases with Day 1, 29 anti-
body marker data included, and N for Cases for Day 57 marker analyses is the number of vaccine breakthrough cases with Day 1, 29, 57 antibody
data included. See fig. S2.
CI, confidence interval; GM, geometric mean; GMC, geometric mean concentration; GMT, geometric mean titer.

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Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial
Peter B. GilbertDavid C. MontefioriAdrian B. McDermottYouyi FongDavid BenkeserWeiping DengHonghong ZhouChristopher R.
HouchensKaren MartinsLakshmi JayashankarFlora CastellinoBritta FlachBob C. LinSarah O’ConnellCharlene McDanalAmanda
EatonMarcella Sarzotti-KelsoeYiwen LuChenchen YuBhavesh BorateLars W. P. van der LaanNima S. HejaziChuong
HuynhJacqueline MillerHana M. El SahlyLindsey R. BadenMira BaronLuis De La CruzCynthia GaySpyros KalamsColleen
F. KelleyMichele P. AndrasikJames G. KublinLawrence CoreyKathleen M. NeuzilLindsay N. CarppRolando PajonDean
FollmannRuben O. DonisRichard A. Koup, and Oleg Borisov, and Brett Chromy, and Mark Delvecchio, and Tremel Faison,
and Corey Hoffman, and Tom Hu, and Pennie Hylton, and Aparna Kolhekar, and James Little, and Jeanne Novak, and Carol
Sabourin, and Evan Sturtevant, and Xiaomi Tong, and John Treanor, and Danielle Turley, and Leah Watson, and Gian King,
and Andrew Li, and Najaf Shah, and Smruthi Suryaprakash, and Jue Xiang Wang, and Patricia D’Souza, and Janie Russell,
and David Beaumont, and Kendall Bradley, and Jiayu Chen, and Xiaoju Daniell, and Thomas Denny, and Elizabeth Domin, and
Kelsey Engel, and Wenhong Feng, and Juanfei Gao, and Hongmei Gao, and Kelli Greene, and Sarah Hiles, and Leihua Liu,
and Kristy Long, and Kellen Lund, and Francesca Suman, and Haili Tang, and Jin Tong, and Olivia Widman, and Christopher
S. Badorrek, and Gregory E. Rutkowski, and Akua Abrah, and Obrimpong Amoa-Awua, and Manjula Basappa, and Robin
Carroll, and Erykah Coe, and Jevone Fentress, and Suprabhath Gajjala, and Nazaire Jean-Baptiste, and Christopher Moore,
and Mursal Naisan, and Muhammed Naqvi, and Sandeep Narpala, and Abhinaya Srikanth, and Clare Whittaker, and Weiwei
Wu, and Shu Hahn, and Di Lu, and James Zhou, and Jessica Andriesen, and Andrew Fiore-Gartland, and Ying Huang, and
Yunda Huang, and Ellis Hughes, and Ollivier Hyrien, and Holly E. Janes, and Michal Juraska, and April K. Randhawa, and
Brian Simpkins, and Brian D. Williamson, and Michael P. Fay, and Martha Nason, and Marco Carone, and Kendrick Li, and
Wenbo Zhang, and Alex Luedtke, and Iván Díaz, and Atoya Adams, and Eric Miller, and Bruce G. Rankin, and John Hill, and
Steven Shinn, and Marshall Nash, and Sinikka L. Green, and Colleen Jacobsen, and Jayasree Krishnankutty, and Sikhongi
Phungwayo, and Richard M. Glover II, and Stacy Slechta, and Troy Holdeman, and Robyn Hartvickson, and Amber Grant, and
Terry L. Poling, and Terry D. Klein, and Thomas C. Klein, and Tracy R. Klein, and William B. Smith, and Richard L. Gibson, and
Jennifer Winbigler, and Elizabeth Parker, and Priyantha N. Wijewardane, and Eric Bravo, and Jeffrey Thessing, and Michelle
Maxwell, and Amanda Horn, and Jennifer Whitaker, and Catherine Mary Healy, and Christine Akamine, and Laurence Chu,
and R. Michelle Chouteau, and Michael J. Cotugno, and George H. Bauer Jr., and Greg Hachigian, and Masaru Oshita, and
Michael Cancilla, and Deborah Murray, and Kristen Kiersey, and William Seger, and Mohammed Antwi, and Allison Green,
and Anthony Kim, and Michael Desjardins, and Jennifer A. Johnson, and Amy Sherman, and Stephen R. Walsh, and Judith
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and Douglas Scott Denham, and Thomas Weiss, and Ayoade Avworo, and Parke Hedges, and Cynthia Becher Strout, and
Rica Santiago, and Yvonne Davis, and Patty Howenstine, and Alison Bondell, and Kristin Marks, and Grant Ellsworth, and
Tina Wang, and Timothy Wilkin, and Mary Vogler, and Carrie Johnston, and Jessica G. Andriesen, and Gail Broder, and
Niles Eaton, and Huub G. Gelderblom, and Rachael McClennen, and Nelson Michael, and Merlin Robb, and Carrie Sopher,
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Sheetal Kandiah, and Carlos del Rio, and Nadine Rouphael, and Paulina Rebolledo, and Srilatha Edupuganti, and Daniel
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Krista Forster, and Jeanette Dickhaus, and Marcia Bernard, and Erica Sanchez, and Nikki Abels, and Cynthia Kunakom, and
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