WHO COVID-19 Vaccines Research

Will emerging data allow increased reliance on vaccine immune responses for public health and regulatory decision-making? 3 September 2021, virtual consultation Geneva, Switzerland

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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Table of Contents TABLE OF CONTENTS .............................................................................................................................................2

EXECUTIVE SUMMARY ............................................................................................................................................3

INTRODUCTION ........................................................................................................................................................4

WHAT IS THE EXPECTED ROLE OF CORRELATES OF PROTECTION IN THIS PANDEMIC? ....................................................5

SESSION 1. EMERGING EVIDENCE ........................................................................................................................6

RCTS REPORTING CLINICAL ENDPOINTS FOR VARIANTS ...............................................................................................6 OBSERVATIONAL STUDIES REPORTING CLINICAL ENDPOINTS FOR THE DELTA VARIANT ...................................................6 EFFICACY AND EFFECTIVENESS AGAINST VARIANTS .....................................................................................................7 OVERVIEW OF HUMAN CHALLENGE STUDIES ................................................................................................................8 STUDIES GENERATING BOTH EVIDENCE ON BREAKTHROUGH INFECTIONS AND IMMUNOGENICITY ....................................8 ASSAYS DEVELOPMENT .......................................................................................................................................... 10 OVERVIEW OF ANIMAL STUDIES REPORTING ON IMMUNOLOGICAL ENDPOINTS ............................................................. 10 OVERVIEW OF STUDIES REPORTING T-CELL RESPONSES .......................................................................................... 11 AVAILABLE DATA AND PLANS TO GENERATE ADDITIONAL DATA ................................................................................... 11 DOES EMERGING DATA ALLOW INCREASED RELIANCE ON VACCINE IMMUNE RESPONSES FOR POLICY DECISION-MAKING? ............................................................................................................................................................................. 12

SESSION 2. CURRENT PROPOSALS FOR REVIEW AND SYNTHESIS OF THE EVIDENCE .......................... 13

INITIATIVES TO ANALYZE AND SYNTHESIZE AVAILABLE DATA ...................................................................................... 13 POTENTIAL FOR AUGMENTING INFORMATION ABOUT CORRELATES OF PROTECTION AND RELIABLY ESTABLISHING

CORRELATES OF PROTECTION ................................................................................................................................. 14 DOES EMERGING DATA ALLOW INCREASED RELIANCE ON VACCINE IMMUNE RESPONSES FOR REGULATORY DECISION-MAKING?................................................................................................................................................................ 15 WHAT IS THE RESEARCH AGENDA MOVING FORWARD? ............................................................................................. 16

CONCLUSIONS ...................................................................................................................................................... 17

WHO R&D BLUEPRINT SECRETARIAT ............................................................................................................... 18

APPENDIX I: AGENDA........................................................................................................................................... 18

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

public health and regulatory decision-making?

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Executive Summary More than 4.8 billion doses of COVID-19 vaccine have been administered globally. While this

itself an important success, equity of access remains an issue. 140 countries have vaccinated

at least 10% of their populations, which was the end of September 2021 goal outlined by Dr.

Tedros, but only 4 of these countries are on the African continent. In order to achieve future

targets, 40% access by the end of 2021 and 70% access by mid-2022, the WHO and all

partners need to find ways to scale up production and increase access to COVID-19 vaccines

as quickly as possible.

Correlates of protection (CoP), immune markers that predict clinical protection against

infection or disease for a given pathogen, can sometimes be used to support efficacy of

second generation vaccines or to bridge existing vaccines to new populations or for variant

modifications where large phase 3 clinical trials are not feasible. A growing amount of

evidence in animal studies and humans suggests that neutralizing antibodies, and to some

degree T cells, play an important role in prevention of symptomatic clinical disease for

currently licensed vaccines. There is less confidence in identification of immune markers that

predict protection against severe disease (where T cells are postulated to play a greater role)

or likely duration of protection. Recent advances in antibody assay standardization have

made comparison across studies possible, though much of the existing data supporting these

conclusions is not well standardized.

Limited information is available on the relationship between humoral immune responses and

protection against specific variants of concern. Nonetheless, it appears that relative titers

against different variants are similar for different spike protein based vaccines. Additional data

are needed to study the association between antibody responses and protection against the

SARS-CoV-2 Delta variant. Modelling approaches will likely be helpful in predicting the

relationship between immune responses and protection against Delta. Outside of Phase 3

studies, large simple randomized trials may also be used during national roll-out to accumulate

additional information on efficacy and immunogenicity.

Most regulators agreed that despite limited data available for the Delta variant, there is robust

evidence to support the use of immune markers to bridge to second generation vaccines that

are based on the same platform, or to other populations. While several key questions remain

regarding the threshold of protection, the role of different immune markers for infection,

severe disease, and duration of protection, and how variants or new vaccine platforms may

influence the CoP, there is increasing openness to the idea of using immunogenicity data as a

basis for inferring protection in additional settings, potentially including new vaccines. The

choice of immune markers, comparator vaccine, and statistical criteria is likely to be made on

a case-by-case basis depending on the characterization of the immune response from the

vaccine candidate and the availability of comparator vaccines in-country. In addition, there

should be plans for post-deployment assessment of effectiveness of any vaccines made

available on the basis of immune markers.

The use of immune markers to predict protection could be furthered by increased use of well

standardized assays and since the previous meeting held 26 May 2021, significant progress has

been achieved and these continued efforts to share results will support policymakers and

regulators in evidence-based decision-making.

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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Introduction The WHO stands by the principle that nobody is safe until we are all safe. To date, globally, 4.8

billion doses of COVID-19 vaccine have been administered. 140 countries have vaccinated at

least 10% of their populations, which was the end of September 2021 goal outlined by Dr.

Tedros, but only 4 of these countries are on the African continent. A continued commitment to

equity in access to COVID-19 vaccine is critical. In order to achieve future targets, 40% access

by the end of 2021 and 70% access by mid-2022, the WHO and all partners need to find ways

to scale up production and increase access to vaccines as quickly as possible. This

consultation on correlates of protection (CoP) intends to ensure that those in the global south

and in low- and middle-income countries (LMICs) have access to safe vaccines that are

properly evaluated.

The WHO has convened regular global consultations to discuss critical scientific issues and to

move the research agenda forward. At the time of the previous CoP meeting, held on May

26, 2021, there was growing evidence that neutralizing antibody (nAb) responses could be

useful in predicting vaccine-induced protection, with the caveat that estimates of vaccine

efficacy (VE) had large confidence intervals and unstandardized assays made it difficult to

have full confidence in results. A strong recommendation was to use standardized assays,

ideally using the WHO international standard. There was high confidence in using humoral

immune markers to predict short-term protection for bridging to different subgroups using the

same vaccine (which has since started for pediatric populations) or bridging to clinical data

for a booster or modified vaccine. There was lower confidence in using humoral immune

markers to predict short-term protection for bridging to clinical data for different vaccines of

the same or different types, or disease caused by variants. There was very low confidence in

using immune markers to predict durable protection or protection against severe disease. It

was proposed to address these uncertainties through greater stringency of comparisons, using

post-authorization real-world data, and collection of additional clinical, animal, and

immunological data.

Since that meeting, new data are available with more information about protection from

variants, individual-level protection, and immune mechanisms of protection. Additionally,

human challenge studies have been initiated and assays are better understood. There is also

increasing appreciation that CoPs are needed to predict durability of protection as we think

about the possible need for a booster, protection against severe disease as there is increasing

recognition that vaccines may not be able to completely protect against mild disease, and

protection against evolving variants.

The objectives of this meeting were to review progress since the last meeting, including how

immunobridging could help to increase vaccine availability, and to identify research gaps

that, if addressed, could support increasing reliance on immune responses to support decision-

making in support of public health.

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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What is the expected role of correlates of protection in this pandemic? A CoP is an immune response that is statistically associated with protection against infection or

disease with a specific pathogen. Different types of CoPs include an absolute correlate

(specific level or threshold of response highly correlated with protection), relative correlate

(level of response variably correlated with protection), and co-correlate (one of two or more

factors that correlate with protection in alternative, additive, or synergistic ways). CoP can be

mechanistic in that the immune response is responsible for protection or non-mechanistic

(formerly called surrogate) in that the immune response substitutes for the true immunologic

CoP which may be unknown or not easily measurable. CoPs are determined through various

means: levels of passively administered or maternal antibody that protect, analysis of immune

responses in protected and unprotected subjects in efficacy trials, observations made on

vaccine failures or immunosuppressed individuals, in human challenge studies, or extrapolated

from animal challenge studies.

A CoP could potentially enable understanding of the likely efficacy of a new COVID vaccine,

the risk of COVID disease for a vaccinee, the risk of disease in a vaccinated population, lot-to-

lot consistency, and could support the licensure or authorization of a vaccine if efficacy trials

become infeasible. There are many potential protective adaptive immune mechanisms

induced by vaccination that could be considered for evaluation as CoPs – various serum

antibody subclasses, mucosal antibodies, CD4+ T cell and CD8+ T cells. The more we learn

about the immune system the more possibilities there are.

Ten principles were outlined regarding CoPs:

1. Must define – protection against what? Infection? Disease? There may be different

CoPs for different clinical endpoints. An example was given for polio.

2. The mechanism of protection against infection is not the same as the mechanisms of

recovery from infection.

3. A large challenge dose can overcome immunity – which is a possibility with the Delta

variant.

4. Most current vaccines protect through antibodies.

5. Correlates may be relative with no sharp distinction between immunity at different

levels; e.g., high titers may protect against infection while lower titers will also protect in

some.

6. Functional antibodies may be better correlates of protection than non-functional

antibodies; for example, in meningococcal infection protective bactericidal antibodies

are needed

7. More than one factor may protect as co-correlates, for example in influenza both

antibodies and cellular immune factors are important for protection.

8. Memory may be a mechanistic CoP, for example Hepatitis B antibodies fade over time

but memory responses prevent disease if a vaccinated individual is exposed.

9. T cell responses may also be important correlates, but these have not been well

defined.

10. Non-mechanistic CoP are useful, for example zoster vaccine is highly protective based

on T cells but antibodies can be measured as a proxy for protection.

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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The immune system is redundant, and we frequently have situations where more than one

type of response correlates with protection and multiple markers can be measured. Current

studies stress the importance of antibodies, and we will likely hear modifications as new

evidence emerges due to the complexity of the immune system.

Session 1. Emerging Evidence RCTs reporting clinical endpoints for variants The COVID-NMA (https://covid-nma.com) is an international research initiative supported by

WHO and Cochrane to provide a live mapping of COVID-19 trials. As part of the COVID-NMA

living systematic review, an update of all randomized evidence on efficacy against variants of

concern (VOC) was provided. As of September 2021, 323 registered randomized controlled

clinical trials (RCTs) have assessed COVID-19 vaccine efficacy, with 60 RCTs published. Of

these 7 RCTs report data on VOCs. Two RCTS are available for Alpha, both against

symptomatic confirmed COVID-19 and 3.5-4 months of follow-up. Novavax showed 86.3%

efficacy and AstraZeneca showed 70.4% efficacy. There was some concern on risk of bias in

both studies because they were post-hoc analyses which led to missing data on sequences.

Four RCTs are available for Beta, all against symptomatic confirmed COVID-19 with follow-up

ranging from 1 month to 4 months. Vaccine efficacy (VE) ranged from 10% for the

AstraZeneca vaccine to 100% for the Pfizer/BioNTech vaccine. Similar to Alpha, all had some

concern for risk of bias due to post-hoc analyses. The AstraZeneca study in particular had

large confidence intervals due to a small sample size. One RCT is available for Delta and the

Bharat Biotech vaccine, with symptomatic confirmed COVID-19 as the outcome with 3.3

months of follow-up. VE was 65.2% with some risk of bias because it was a post-hoc analysis.

Overall, there is limited evidence from RCTs on VOCs and consistent methodological issues

including post-hoc analyses that lead to lack of power, missing outcome data due to lack of

sequencing and, heterogeneous measurements of outcomes (both direct and indirect

evidence). Continued observational studies are needed to provide further evidence.

Observational studies reporting clinical endpoints for the delta variant As part of COVID-NMA, 127 observational studies on VOC have been identified, 100 have

relevant outcomes to assess VE and 28 are studies on the Delta variant. Of those, 13 meet the

strict eligibility criteria including using a control/non-vaccinated group to estimate vaccine

effectiveness and with some attempt to control confounding. These studies are cohort and

test-negative case-control studies conducted in the general public and in healthcare workers

taking place in India, Canada, the USA, UK, Qatar, Scotland, and Israel. After two doses, VE

against Delta SARS-CoV-2 infection (asymptomatic or symptomatic) was about 60-86%, with

no meaningful differences between vaccines (AstraZeneca, Pfizer, Moderna, Coronavac). As

expected, after only one dose, VE was lower than after two doses. After two doses, VE against

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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symptomatic Delta SARS-CoV-2 infection increased relative to any infection. VE against severe

COVID for Delta was 80 - >90%.

When interpreting results from observational studies we need to think about the limitations and

inevitable risks of bias. Confounding occurs when there is a common cause of both whether

someone is vaccinated or whether someone has the outcome (asymptomatic infection,

infection, severe disease). With RCTs the chance of vaccination is randomized, and this is not a

concern. In observational studies confounders can induce bias if not accounted for in the

study design or analysis. Known confounders include age, sex, socioeconomic status, ethnicity,

comorbidities, geography, special populations, calendar time to reflect changing incidence

of virus, hospitalization and need for healthcare, symptoms at time of planned vaccination,

and health-seeking behavior. Some confounders, such as symptomatic at time of vaccination,

can be difficult to address if the data is not collected. Healthcare seeking behavior is likely

defined by an unmeasurable set of personal characteristics. The test-negative design

attempts to ameliorate confounding due to health-seeking behavior by restricting the analysis

to those who are tested (compare vaccination history in those who test positive and who

those who test negative) but this design can still introduce spurious associations and potential

selection bias. Other key problems in observational studies include missing data, recall bias

from self-reported vaccination history, and a lack of prospectively defined protocols or

analysis plans that may allow authors to cherry pick findings. With these key limitations the

direction of potential bias in these studies can be difficult to predict.

Efficacy and effectiveness against variants A broad overview of available reports of vaccine efficacy in RCTs and informal non-peer-

reviewed reports of observational studies was outlined. There are limitations with a broad

approach in trusting non-peer reviewed results, but this was meant to see what trends could

be identified from crude averages with a careful eye on data sources. 29 reports provided

outcomes on vaccine efficacy against severe disease and any COVID infection. Inverse-

variance-weighted averages were calculated to look at trends among reported VE against

any infection, by variant, by vaccine type, and by length of follow-up time. When trials were

grouped by reported VE against any infection, all studies showed increased VE against severe

disease relative to any infection and all VE against severe disease at 90% or above. Even those

moderately protected against infection showed good protection against severe disease. The

same trend was observed when organized by variant with Delta (12 studies) VE against

infection at about 80% but against severe disease at about 90%. The same trend was seen by

type of vaccine (viral vector, inactivated, protein subunit, mRNA) and by follow-up time,

though there was less detail available on duration of protection. Overall, there was

consistently greater VE against severe disease than against any infection. While some

vaccines work better than others, they all work well with substantial VE against all variants that

persists for many months.

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

public health and regulatory decision-making?

September 3, 2021

Overview of human challenge studies Volunteer challenge studies are a powerful and useful tool that can provide an extraordinary

amount of information. A challenge model for SARS-CoV-2 could estimate infective inoculum,

assess infection-derived immunity, characterize the immune response, obtain a preliminary

measurement of VE, and identify a correlate of protection as each person serves as their own

baseline. There are certain criteria that describe if a pathogen is amenable to this model

including: clinical severity of natural disease, if the illness is treatable, if the illness is reliably self-

limited, the risk to the community, if physical containment or quarantine is required,

documenting the subject’s baseline health, and that follow-up can be assured.

Early in the pandemic there was discussion about human challenge studies, but these were

not pursued due to ethical and logistical concerns. WHO put together two committees to

discuss the ethics of the challenge studies and the practicalities and feasibility of what it might

take to have this type of model. Factors that warrant special caution with SARS-CoV-2 include

high transmissibility, severity in certain sub-populations, the need for a high containment facility

to prevent transmission, occasional extended disease in young adults (Long COVID), and the

debate on reliability of a rescue treatment.

The advisory group recommended incremental stepwise preparation of the model starting

with a conversative approach among only 18-25 year-olds with high-level compulsory isolation

and selecting isolates for BSL-3 GMP manufacture using a frozen liquid formulation in vials

starting at 1x102 TCID50. There are four groups that either have or intend to have a model. In

the UK colleagues at Imperial College and Oxford worked with the CRO hiVivo to establish a

model and started in Q2 2021. They are currently in the dose escalation phase infecting

previously infected subjects, none of which are vaccinated, and only using the Wuhan strain.

Most infected volunteers are mildly symptomatic and use pre-emptive therapy should these

become anything more than mild. Groups in the Netherlands and the US do not have

government approval but have plans in place. A group in Belgium will build a new facility that

is ready at the end of 2022.

Results of these studies can help answer questions that cannot be answered in other ways.

Unfortunately, human challenges not yet proven to be nimble taking 4-6 months to make up

GMP lots. These studies could be useful for additional COVID-19 vaccines delivered by the

intranasal route since there is a correlation between mild and severe disease.

Studies generating both evidence on breakthrough infections and

immunogenicity Three presentations were given to describe studies generating evidence on breakthrough

infections and immunogenicity.

In the Moderna COVE trial, a case-cohort sampling approach was used to assess antibody

marker correlates against the COVID-19 primary endpoint. Four antibody markers were

assessed – binding antibody (bAb) to the Spike protein, bAB to the Receptor Binding Domain

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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(RBD), pseudovirus (PsV) nAB ID50, and PsV ID80 titers, standardized to the WHO international

standard. Markers were assessed at day 29 and day 57. There was a high correlation of bAB

Spike and bAB RBD responses and high correlation of PsV nAB cID50 and cID80 responses (ID50

and ID80 responses calibrated to the WHO International Standard. Across all markers and time

points, the geometric mean titers (GMTs) were lower in cases than non-cases. The hazard ratio

of COVID was lower for higher antibody levels in vaccinees and was consistent across all

markers. There is likely no threshold of antibody that is protective, but rather the greater the

antibody response, the greater the level of clinical protection. For the causal mediation

analysis, day 29 cID50 titers and cID80 titers explained about 68.5% and 48.5% of the total risk

attributable to the marker. If circulating nAb at day 29 were removed, but the other

consequences of vaccination remained, overall VE would be expected to reduce by 68.5%,

from 92.3% to 56.0% on the log scale. This is comparable to the proportion of VE mediated by

HAI titers for inactivated flu vaccine. Although confidence intervals around the estimates are

wide, this suggests that nAb may not fully mediate the VE of the Moderna vaccine against

COVID-19, and additional markers might be able to increase the predictive accuracy of the

model. Other assays may also be needed to improve sensitivity to detect the lowest levels of

neutralization activity. The data also suggest that Day 29 markers are at least as strong

immune correlates as Day 57 markers which could lead to more practical endpoints and

faster immunogenicity trials. The main limitations of this analysis were there were no other

markers of interest assessed and there was no information on Delta. The study helped identify

a statistical CoP but cannot prove a mechanistic CoP given limited experimental control and

reliance on causal assumptions.

The Oxford Vaccine Trial group conducted a similar analysis from the adenovirus-vectored

vaccine UK phase 2/3 study and compared results to the Moderna analysis. In both studies

titers were converted to WHO standard units to allow for easy comparison though there are

critical study differences including vaccine types, population age and ethnicity, and

endpoints. For the nAb, the range of titers was different, with the Moderna vaccine achieving

greater antibody responses, but when the plots are compared the thresholds for 70% and 90%

VE are similar (1:8 and 1:4 for 70% efficacy for ChAdOx1 and Moderna respectively, and 1:140

and 1:83 for 90% efficacy for ChAdOx1 and Moderna respectively). For anti-spike IgG results

were not as similar, though confidence intervals were wide, and the Oxford vaccine had IgG

results that had a reduced lower bound.

The third speaker outlined results from studies of the Sputnik V vaccine in Argentina. While

authorized in 50 countries, with substantial use in South America, there have been few

independent studies conducted of this vaccine. A cross-sectional study conducted in

healthcare workers found that 42% had RBD titers before vaccination. While titers peak at one-

or two-weeks following vaccination, it is unclear if this will protect from disease and for how

long. In another study among previously infected participants, after the first dose the RBD

binding was high. Neutralization assays against variants were also conducted and showed

similar results, with an increased response in those previously infected.

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

public health and regulatory decision-making?

September 3, 2021

Assays Development Two laboratories are supporting vaccine manufacturers with pseudovirus neutralization (PsV)

assays (Duke serves Moderna, Monogram serves Janssen, Novavax, AstraZeneca, and Sanofi).

FDA has reviewed the validation of both assays which use similar technologies (lentivirus

backbone, full-length spike, luminescence, and transfection) but generate a 3-fold difference

in titers for convalescent and vaccine sera. This may be due to differences in PsV production –

Duke uses cells expressing TMPRSS2. Calibration is needed to support decision-making based

on data from these two assays including identifying immune correlates, licensure,

immunobridging regulatory approvals, and boosting decisions.

Three sample sets were used including convalescent sera from early in the pandemic, samples

from recipients of the Moderna vaccine, and the WHO International Standard (WHO-IS). Three

calibration approaches were used; 1) calibrate to WHO-IS, 2) calibrate to the convalescent

sera using bivariate normal distribution, and 3) calibrate to convalescent sera using linear

regression. As expected, the ID50 titers were consistently 3-fold higher in the Monogram assay

compared to Duke. All three calibration approaches worked well to bring these into

equivalence with the greatest concordance correlation coefficient using the second method

(CCC: 0.87), though the WHO-IS also performed well (CCC: 0.75). Comparisons were made

using the arithmetic mean, geometric mean and median and the arithmetic mean performed

the best.

Overview of animal studies reporting on immunological endpoints The first non-human primate (NHP) studies conducted in 2020 showed that vaccines led to

protection at a reasonably high level. Initial correlates analyses demonstrated nAbs and bAbs

correlated inversely with peak viral loads in nasal swabs and bronchoalveolar lavage. In an

IgG adoptive transfer study examining the mechanisms of protection, purified IgG from

convalescent macaques was given to naïve animals to determine if this protected animals,

and if so to define a NAb threshold for protection. A dose-dependent response was observed

where the highest dose completely protected animals, the lowest didn’t protect but showed

lowered peaks and faster resolution of virus. This showed that antibodies, even isolated from

other immune components, could provide protection. A CD8 T cell depletion study was also

conducted to determine the role of CD8 T-cell-dependent responses in protection again re-

challenge. CD8 T cell depletion reduced protection against re-challenge in those subjects

with waning Ab titers. This data suggested that Abs alone can protect, but also that cellular

immune responses contribute to protection when Ab titers are borderline or sub-protective.

The levels seen in animals are not too different than what is seen as protective levels in humans

with the Moderna and Oxford studies.

To date, all data has been based on the ancestral sequence and these early studies may not

apply with VOCs. Studies show reduced responses to Beta and Delta for Pfizer, Moderna, and

J&J vaccines. bAb and nAb protective thresholds will likely be different for variants, especially

those with increased transmissibility such as Delta. Antibody responses do not appear to fully

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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September 3, 2021

explain early protection by COVID-19 vaccines or protection against variants, suggesting that

cellular immune responses may also contribute to protection.

Overview of studies reporting T-cell responses For any virus that is susceptible to nAb, they are the first line of protection and are the only

mechanism that can provide truly sterilizing immunity. Thus, for these viruses, vaccines that

induce high level, long lasting neutralizing antibodies are likely to be most effective. There are

also additional lines of defense as antibody levels are correlated with CD4 T cells and are a

surrogate marker of vaccine-specific TFH cells (T follicular helper cells). There are various lines of

evidence that point to substantial protective contributions of T cells including: T cell correlation

with better outcomes and lower viral loads, CD8 T cells providing control in monkeys,

monoclonal antibody clinical trials, the observations that those with low antibody responses

can still have reasonable protection, 1-dose protection of Moderna or Pfizer vaccines in the

absence of detectable nAb, and kinetics, and tissue distribution of COVID-19. Viral infection

occurs quickly in the nose and mouth but slowly in the lungs implying a link to cell mediated

responses. Three new datasets all show that pre-existing cross-reactive T cells result in better

antibody and T cell responses to vaccines.

It is reasonable to consider that hospitalization from COVID-19 is prevented by a combination

of protection provided by antibody, CD4, and CD8 T cells. Antibodies are a major contributor

to detectable infection, but all parts of the immune system likely work together to prevent

hospitalization and death. T cell responses may be a bigger contributor when antibody titers

are low, when they decline following vaccination, among certain immunocompromised

individuals, or if there is nAb escape against variants. These markers also become more

important with novel vaccines that have T cell dominant mechanisms of action. T cells can be

measured as potential correlates of immunity, as has been done for HIV vaccines, but has not

been done for COVID-19 vaccines. Evidence lags because T cell studies are more resource

intensive, more challenging to standardize, passive transfer proof-of-concept studies are not

available, and due to complexities of T cell contributions by type and location.

Available data and plans to generate additional data Several developers outlined their plans to assess CoP in ongoing studies – details are found in

the slides linked below. Highlights include the following:

- Vaxine’s recombinant protein-based vaccine found that during challenge studies

protection was observed in several animal models, but neutralization markers did not

correlate with protection.

- GenoImmune’s vaccine protected against severe illness from the Delta variant despite

reduced nAb, indicating the possible role of cell-mediated immunity.

- Medigen’s conducted an immunobridging study comparing their subunit protein

vaccine to AstraZeneca and an EUA moved forward in July with a post-marketing

commitment to study vaccine effectiveness and pharmacovigilance.

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- Nanogen’s subunit vaccine is undergoing Phase 3 studies with planned PRNT assays by

variant.

- Cellid is planning for an immunobridging study comparing their adenovirus vectored

vaccine to the Janssen vaccine.

- Studies from Janssen show nAb responses are maintained for at least 8 months after a

single dose and a rapid anamnestic response after boosting, even against VOCs.

- Moderna is conducting a phase 2/3 study in healthy adolescents and the study met the

primary immunogenicity endpoint where adolescent nAb titers were non-inferior to

those of young adults (VE: 93-100%, depending on case definition).

- Providence Therapeutic’s lipid nanoparticle-formulated vaccine showed strong nAb

against VOCs which is comparable to approve mRNA vaccines.

- VIDO’s subunit vaccine achieved strong antibody responses in phase 1 studies that

correlate with animal studies.

- City of Hope’s synthetic viral vector vaccine will be evaluated in immunocompromised

patients and compared to the Pfizer vaccine in patients with post cellular therapy for

hematological malignancies.

Does emerging data allow increased reliance on vaccine immune

responses for policy decision-making? Experts discussed if there was sufficient information to use available data to inform policy

decisions, what the current data suggested, limitations of current data, and what additional

data is needed.

All experts were optimistic and agreed that current results are promising. Induction of

antibodies, most likely nAb and at times bAb, can prevent infection in the lower respiratory

tract if titers are high enough. T cells likely play a role in controlling for replication if infection

takes place to prevent severe disease. Many questions remain but this relationship is well

characterized for the purposes of immunobridging studies and getting vaccines licensed.

Though there was caution that with Delta the CoP could behave differently, additional data

from ongoing clinical trials and observational studies will help us understand what levels are

needed to achieve protection in the context of new VOCs.

Remaining questions were related to an unknown, absolute correlate threshold, how a third

dose as either a booster or in the primary series would prolong or broaden immune response,

and what level of immune response would require a booster. There was also discussion on

prevention of infection in the upper respiratory tract compared to the lower respiratory tract.

Others wanted more information on the role of T cell responses and the driver of protection in

the absence of neutralization which could be especially useful if we see escape from

Flinders University

Geno Immune Medigen Nanogen Cellid

Johnson & Johnson

Providence Therpeutics

VIDO City of Hope

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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neutralization for variants in the future. Experts noted that without standardization across

cellular immune studies, comparison and integration of results from different studies are

difficult. Animal models could be used to move the vaccine development pipeline forward

and answer some of these remaining questions.

There was an important reminder that policy decision-making depends on the context - with

LMICs focusing on approval towards vaccines preventing severe disease and high-income

countries also considering how vaccines may prevent infection and transmission, though data

on these outcomes are limited. These endpoints are likely to have different CoPs. There was a

recommendation to have an immunobridging toolkit where developers should consistently

provide a packet of information to see the breadth of immune response produced – across

VOCs, using WHO reagent panels of sera, standardized pseudoviruses, standard proteins for

binding assays, and reagent toolkits to better compare vaccines. In general, the community

needs to be flexible and not focus only on nAb but look at a broad range of responses to mine

for mechanistic correlates of immunity.

Session 2. Current proposals for review and synthesis of the evidence Initiatives to analyze and synthesize available data Three presentations were given to describe initiatives to analyze and synthesize available

data.

A model was previously developed to predict protective efficacy in phase 1-3 trials based on

the mean and distribution of nAb titers. This analysis was adapted to predict protection against

VOCs. Neutralizing activity against the ancestral SARS-CoV-2 can be used to predict

neutralization of the VOC, with all examined vaccines showing similar drops in neutralization to

the variants (Alpha 1.6 old, Beta 8.8 fold, Delta 3.9 fold). Adapting the curves based on VOC

resulted in 13/14 studies falling within the 95% CI of the study VE. This same method could be

used to predict efficacy of a new vaccine by estimating neutralization against the ancestral

virus and benchmarking in the same assay to different vaccines to use as marker points. The

same could potentially be done with a new variant to estimate the fold-drop compared to

the ancestral strain to know how much to shift the curve. It was noted that the model

continues to work well despite the increased rapidity of Delta infection compared to other

variants.

The second presentation built on previous work that showed the relationship between efficacy

and nAb or bAb. The first studies had to be expressed as a ratio of GMTs to convalescent

patients, but the current studies standardized results in a convenience sample of SARS-CoV-2

naïve subjects donated as part of national rollouts instead of a clinical trial. Results showed

strong correlations between binding Ab to spike and RBD. Spike IgG binding levels explained

97.4% of the variance in VE. Binding antibodies to Spike and RBD were correlated with nAb. A

population-based approach, as seen with pneumococcal conjugate vaccine (PCV), could

be used to relate the observed distribution of Ab in a subset of the immunized population to

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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the observed point estimates of VE against disease. For PCV, trials were pooled, and a

universal CoP was generated which was used by manufacturers and licensing authorities.

Reverse cumulative distribution functions were estimated from spike IgG in those who received

each COVID-19 vaccine and a published VE was used to compute a protective threshold.

These could be used in head-to-head comparisons of licensed vaccines and a comparator to

look at the proportion of seroconversion above a threshold or a comparison of GMT. GMT may

be important since mRNA vaccines induce a high antibody response compared to other

platforms. For VOCs we need assay standardization and to focus on the quantitation of

antibodies to VOC.

The third presentation outlined plans of the USG efforts to develop a CoP. Efforts have begun

to harmonize correlates analyses among the 5 USG supported phase 3 trials and additional

collaborations with other studies to enrich the meta-analysis dataset. Analyses planned during

blinded phase 3 periods include: assessing early Ab biomarkers as types of correlates for risk

and protection, assessing Ab biomarkers over time as immune correlates of risk and

protection, sieve analyses of viral sequences in phase 3 trials, correlates of risk (CoR)/CoP of

various study endpoints (asymptomatic, infection, severity), and sieve analysis for different

VOC/VOI. There will be a meta-analysis with large amount of data, heterogenous immune

markers and host characteristics to validate immune marker models predicting VE.

During post unblinding/cross-over periods planned analyses include examination of early Ab

biomarkers as correlates of risk in breakthrough infections, and Ab biomarkers over time with

several blood draws and stored blood samples. Similar analyses have been done for dengue

and for different serotypes of dengue. In addition to VOC/variants of interest (VOI), additional

analyses may be conducted on other spike-features such as how close the virus is to the

vaccine insert strain based on the sequencing distance. This has been done before for HIV. For

variants that were not circulating during the phase 3 blinding period, such as with Delta,

breakthrough infections in later periods can still be captured to determine correlates of

relative risk. To determine CoP, RCTs would be integrated with observational data to estimate

strain-specific outcome incidence for a counterfactual placebo arm.

Potential for augmenting information about correlates of protection and

reliably establishing correlates of protection Experts discussed potential strategies to establish reliable CoPs including study design and

analysis. Because an immunologic biomarker that is a correlate of risk is not necessarily a CoP,

it could under or overestimate the vaccine’s true clinical efficacy. There are multiple uses of

biomarkers including being used as replacement endpoints for registrational evaluation in

studies to examine booster strategies, modification of vaccine strains for VOCs, extrapolation

to other populations, new vaccines in the same class, and new vaccines in new classes.

Extrapolating to other populations, such as adult to pediatrics, requires evidence that the

biomarker predicts protective effect of immune responses including timing, magnitude, and

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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duration of effect. There should be justification that unintended effects are not substantively

more influential in pediatric settings relative to adults with discussion of the proper dose given

increased safety risks. Future steps for validation of immunologic biomarkers include continued

evaluation of aggregated data from clinical trials to reliably evaluate VE and increase the

number or properly controlled studies of vaccines with immune biomarkers and clinical

endpoints, especially for new vaccines. Standardized assays should also be used to accurately

summarize the immune responses.

Large scale simple RCTs during vaccine roll-out could potentially be used to validate

predictions made using CoP or to validate the CoPs themselves. For example, the order of roll-

out could be randomized at a country level with surveillance systems identifying cases. Trial

researchers would lead planning, implementation, follow-up, and analyses but vaccinees

would have very little difference other than blood draws and potential extra blood draw visit

during follow-up. If there is national-level rollout in a country with a good routine surveillance

system this could be led by the countries themselves.

Placebo controlled RCTs provide the highest level of evidence to establish VE and where

feasible will provide the best evidence to support completely new platform technologies or

alternative routes of administration, in addition to supporting continued efforts to define a

CoP. The humoral response has been accepted for immunobridging within vaccine products

and we are beginning to see consideration of this across platforms as well. Additional data is

needed across variants, clinical endpoints, and population groups. As confidence in the data

increases, it may well be possible to define immune criteria that would allow approval of

vaccines without clinical endpoint data in the future for at least some vaccines, with post

authorization VE studies used to confirm effectiveness. Critical evidence gaps include:

quantitative vs qualitative immune response (relative or threshold), how would CoP translate

to public health relevant endpoints such as disease vs infection/transmission, will CoP allow

information for targeted vaccine recommendations (e.g., age groups), and can CoP predict

duration of the immune response?

Additional efforts should be made to look at passive transfer antibody studies and animal

models. Longitudinal cohorts should continue to collect samples so we can look for additional

CoP specific to a variant in the future as new assays are developed. Also, mucosal Ab may

become more important long-term and muscosal immune responses are not well represented

by serum samples. We need a richer basis of data to do these studies. Finally, good

deployment data can be used to resolve any residual uncertainties from immunobridging

studies and answer other questions, including the need and impact of boosting.

Does emerging data allow increased reliance on vaccine immune

responses for regulatory decision-making? The focus of this panel was how to best use immune markers when there is no CoP or threshold

for benchmarking immunogenicity of vaccines and clinical efficacy studies are not feasible.

Immune markers could potentially be suitable to infer protection by new vaccines if superior

neutralizing antibody response to a candidate vaccine were shown to be comparable or

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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superior to that for a licensed vaccine. Functional antibodies are preferred, and T cells

responses are difficult to use as part of inferential testing, but could be used as supportive

evidence. A June 2021 ICMRA workshop demonstrated consensus that immunogenicity

bridging may be needed in an assessment of second-generation vaccines if efficacy studies

are no longer feasible. Questions remain on which comparator to use, which endpoint

(seroconversion rate and/or GMT), the role of VOCs, comparators for heterologous series, and

how the duration of antibodies determines the role of booster doses.

Most regulators agreed that though there are still issues to address, these are unlikely to

ultimately prevent the use of immune bridging for second generation vaccines. Most decisions

may need to be made on a case-by-case basis depending on the new vaccines – including

the choice of comparator, how cell mediated responses and animal models may be used for

supportive evidence, and the need for post authorization VE studies.

Others commented that recent focus has been on short-term Ab responses, but we need to

better understand waning immunity and a threshold of protection over time. Decisions on

comparators will depend on what is licensed in country and what data is available with a

clear definition of endpoints. Limited availability of comparator vaccines may influence the

feasibility of these approaches.

In China, though immunogenicity may be used to authorize a booster vaccine or modified

vaccine, it is not accepted as surrogate endpoint to extrapolate VE for novel vaccines. New

vaccines on the same platform will still need a clinical endpoint with a comparator.

In Korea, superiority studies are being used to compare a candidate vaccine to AstraZeneca

using nAb responses. Long-term immunogenicity and post-authorization VE studies wlil be

required. In this case the comparison will be made on the ancestral strain and not VOCs.

Overall, there was an openness to using immunogenicity as the basis for inferring protection

with many specific decisions made on a case-by-case basis depending on the mechanism of

action of new vaccines. This helps developers understand what data is needed and can drive

efforts towards regulatory convergence.

What is the research agenda moving forward? Moderators of the panels agreed that there needs to be more evidence generated around

immune responses especially in terms of long-term protection and the CoP related to different

clinical endpoints. There was a comment that emerging data from Israel indicates natural

exposure may confer longer term protection compared to mRNA vaccines and this is not well

understood.

There needs to be continued work on aggregating data from clinical trials and continued well

designed RCTs for new vaccines and classes of vaccines with no CoP. Phase 4 trials at the

national level can also produce information on immunogenicity and VE.

Experts were again optimistic that antibodies can serve as a CoP and existing vaccines work

well to reduce mortality and severe disease.

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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Conclusions Over the years, we have learned quite a bit about correlates of protection that is relevant for

COVID-19. The immune system is complex, but that has not prevented us from identifying

immune markers that predict protection for many vaccines. RCTs showed reduced VE against

Beta and Delta variants compared to previous variants for symptomatic infection, but overall

show that vaccines are still effective against these VOCs. Observational studies, though

subject to important biases, also support the conclusion that vaccines are effective against

the Delta variant for symptomatic and severe disease. Studies have consistently found that VE

against severe disease is greater than against symptomatic disease, regardless of variant,

vaccine time, or time since vaccination. Human challenge studies could also yield important

information but there is limited capacity and production of variant challenge viruses will take

time.

Analyses using RCT data suggests that higher antibody responses are strongly associated with

increased protection from the Washington strain and protection is partly mediated by nAb.

Similar patterns were observed for an adenovirus-vectored vaccine especially with nAb. These

findings are consistent with early animal studies and adoptive transfer experiments. Limited

data is available in human and animal data about the Delta variant. The WHO standard is

now available which makes comparison of nAb assays across studies possible. Nonetheless,

cell-mediated responses are likely to play an important role in the absence of neutralization,

and especially in severe disease, though there is difficulty comparing results across labs

without standardization. More data are needed on variant-specific protection – reagent

toolkits, passive transfer studies in animals of human Ab may be useful.

Studies show that different vaccines maintain consistent drops in titers for VOCs, which have

allowed for scaling of existing models enabling the calculation of a threshold from existing

data and extending it to VOCs. Many analyses are planned from US trials with standardized

assays that may allow prediction of effectiveness against future variants.

Outside of RCTs, post-deployment confirmation, including large simple trials, could be used to

estimate effectiveness, confirm safety, and identify a CoP. Additional clinical data collected

during deployment could also help support the use of correlates in heterologous boosting

schedules.

Regulators are now focusing on the practical aspects of immunobridging, e.g., deciding the

comparator vaccines and criteria for comparisons. Key considerations include variants,

duration of immunity, severity of disease, assay standardization, and the importance of post-

authorization confirmatory studies.

Since the last meeting in May we’ve continued to make progress to better understand CoP

and how they can inform policy and regulatory decision-making. These meetings and

continued sharing of information are critical to bringing this pandemic to a rapid close.

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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WHO R&D Blueprint Secretariat Ana María Henao-Restrepo, Ximena Riveros Balta, Lauren Schwartz, César Muñoz-Fontela,

Neddy Mafunga, Sayyora Esser, Patrick Lydon, and Fatema Kazi.

Appendix I: Agenda Time Topic Speakers

13:00 - 13:10 Welcome address

Objectives of the meeting

WHO

Philip Krause

13:10 – 13:20 What is the expected role of correlates

of protection in this pandemic

Stanley Plotkin

EMERGING EVIDENCE

13:20 – 13:30 RCTs reporting clinical endpoints for

variants

Isabelle Boutron

13:30 – 13:40 Observational studies reporting clinical

endpoints for delta variant

Julian Higgins

13:40 – 13:50 Efficacy and effectiveness against

variants

Richard Peto

13:50 – 14:00 Overview of Human challenge studies Mike Levine

14:00 – 14:20 Studies generating both evidence on

breakthrough infections and

immunogenicity

Peter Gilbert

Merryn Voysey

Benhur Lee

14:20 – 14:30 Assays development David Montefiori

14:30 – 14:40 Overview of animal studies reporting

on immunological end points

Dan H Barouch

14:40 – 14:50 Overview of studies reporting T cells

response

Shane Crotty

14:50 – 15:20 Available data and plans to generate

additional data

(3-5 mins each)

Flinders University - Nikolai Petrovsky

Geno-Immune Medical Institute - Lung-Ji

Chang

Medigen – Allen Lien

Nanogenpharma – Do Minh Si

Cellid - Chang-Yuil Kang

Janssen - Jenny Hendriks

Moderna – Randy Hyer

Providence Therapeutics – Natalia Orozco

Vaccine and Infectious Disease

Organization (VIDO) - Trina Racine

City of Hope Medical Center – Don

Diamond

Others TBC

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WHO COVID-19 vaccines research Will emerging data allow increased reliance on vaccine immune responses for

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15:20 – 15:50 Does emerging data allow increased

reliance on vaccine immune responses

for policy decision-making?

o What the current data suggest ?

o What are the limitations of the

available data?

Panel discussion moderated by

Helen Rees

Stanley Plotkin

Galit Alter

Florian Krammer

Kanta Subbarao

CURRENT PROPOSALS FOR REVIEW AND SYNTHESIS OF THE EVIDENCE

15:50 – 16:20 Initiatives to analyse and synthetize

available data

10 min each

Miles Davenport

David Goldblatt

Peter Gilbert

16:20 – 16:50 Potential for augmenting information

about correlates of protection and

reliably establishing correlates of

Protection

Panel Discussion moderated by Odile Leroy

Thomas Fleming

Ira Longini

Jakob Cramer

Susan Ellenberg

Martha Nason

Philip Krause

16:50 – 17:10 Does emerging data allow increased

reliance on vaccine immune responses

for regulatory decision-making?

(current vaccines, modified vaccines,

new vaccines, mix and match)?

o What data needs to be considered in

the decision making process?

o What preliminary conclusions can be

drawn-up from existing data?

Panel Discussion moderated by Marco

Cavaleri

Marion Gruber – FDA/CBER, US

Boitumelo (Tumi) Semete – SAHPRA, South

Africa

Yalin Liu – NMPA, China

Dean Smith – Health Canada, Canada

In-Sook Park – MFDS, Korea

Representative from Brazil (ANVISA) TBC

17:10 – 17:40 What is the research agenda moving

forward?

Panel discussion moderated by Philip

Krause

Chairs and panelists of previous panels;

Chairs to provide a summary of their panels

17:40 – 18:00 Main conclusions and next steps Philip Krause

18:00 END OF MEETING