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Phase III COVID-19 vaccine data kick-start next phase: mapping efficacy to antibody levels  

Though correlates of protection are still a long way off, the first Phase III data from COVID-19 vaccines launch the process to tie efficacy to antibody titers and T cell responses

Though correlates of protection are still a long way off, the first Phase III data from COVID-19 vaccines launch the process to tie efficacy to antibody titers and T cell responses.

Nov 20, 2020 | 11:09 PM GMT

Efficacy data from the first two Phase III trials of COVID-19 vaccines shattered expectations and validated mRNA as a vaccine modality. The findings also mark the start of the search for correlates of protection.

An analysis of the efficacy results in the context of the vaccines’ immunogenicity in early clinical trials provides the first clues to the humoral and cellular responses needed to protect the population from SARS-CoV-2.

The findings benchmark neutralizing antibody titers in certain assays and call into question the need for strong CD8+ T cell responses in the early weeks of protection.  

Additional insights will be made, and with stronger confidence, as short- and long-term immunogenicity data become available from the Phase III trials of the four front-runner vaccines, which have enrolled tens of thousands of subjects instead of the dozens to hundreds enrolled in the Phase I and II trials. 

The hope is to decipher signals that can serve as surrogate endpoints for future COVID vaccines, and to gather learnings that could generalize to vaccine development for other coronaviruses, including the next strain to make the jump to humans.

mRNA vaccines beat expectations

In September, release of the full Phase III protocols of leading COVID-19 vaccines revealed the vaccine developers were aiming for at least 50% efficacy at final analysis, with higher performance needed to see statistical significance at earlier, interim analyses. 

BNT162b2 from Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) beat its projected efficacy thresholds at interim and final analyses by wide margins; mRNA-1273 from Moderna Inc. (NASDAQ:MRNA) did the same at an interim analysis.

Pfizer and BioNTech reported topline data Wednesday from their completed Phase III trial demonstrating a 95% (p<0.0001) efficacy rate in preventing development of COVID-19 symptoms. The final analysis was triggered by accrual of 170 confirmed COVID cases in the trial, of which 162 were in the placebo arm.

The protection rate was slightly higher than the 90% efficacy the company saw at its interim analysis on Nov. 9 and essentially identical to the interim efficacy reported by Moderna Inc. (NASDAQ:MRNA) on Monday.

Moderna’s efficacy rate was based on an analysis of 95 cases, of which 90 were in the placebo group vs. five in the mRNA-1273 group, for an efficacy of 94.5% (p <0.0001).

Lack of correlation calls for better assays, or other measures

In Phase I trials, mRNA-1273 induced antibody titers that were almost quadruple levels produced by BNT162b2, assessed in similar assays using live virus; yet the two candidates showed almost identical efficacies in Phase III trials. 

While the discrepancy could indicate a ceiling effect was hit at the titers Pfizer and BioNTech observed, it could also reflect a need to optimize the in vitro assay conditions, or that differential T cell responses or other factors are at play.

Both AZD1222 from AstraZeneca plc (LSE:AZN; NASDAQ:AZN) and JNJ-78436735 from Johnson & Johnson (NYSE:JNJ) induced lower titers in their respective assays than the Moderna and Pfizer-BioNTech vaccines.

Phase III readouts from these agents, expected by year end, will add more points to the correlation curve, though  each vaccine developer’s choice to initally use a different assay or set of conditions has made it nearly impossible to directly compare potencies.

Operation Warp Speed is trying to solve that problem by making funding contingent on companies submitting their samples to NIH’s National Institute of Allergy and Infectious Disease (NIAID), where they are run in standardized assays. 

Moderna, AZ and J&J all received Warp Speed funding to develop the vaccines and agreed to use NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-informed harmonized protocols for their Phase III vaccine trials, meaning it should be possible to compare Phase III titers between the trials. Pfizer has a procurement agreement with Operation Warp Speed, which has acquired 100 million doses for the U.S. and can acquire up to 500 million more. 

How T cell responses contribute to vaccine protection isn’t fully understood, but they are thought to be especially important for long-lasting immunity. mRNA-1273 induced weak CD8+ T cell responses in Phase I testing, using the same dose taken into Phase III, but that didn’t stop the vaccine from inducing strong protection in the Phase III trial.  The strength of the CD8+ T cell response in the Phase III study will be important for assessing the cells’ role in efficacy.

Pfizer and BioNTech have not reported T cell responses for BNT162b2, but a slightly different version of the vaccine, BNT162b1, induced CD4+ T cell responses in 100% of subjects and CD8+ responses in 80% of subjects in Phase I testing.

Vaccine potency in older adults

Data are also starting to shed light on how well the COVID-19 vaccines will work in elderly adults, whose immune systems are generally weaker, and who are at higher risk of developing severe disease.

All the vaccine developers that have reported immunogenicity data in different age groups in early-stage trials saw a decline in the elderly, though the degree of decline varied widely.

The Pfizer-BioNTech vaccine showed one of the largest drops in neutralization titers, with a nearly 60% reduction in subjects over 65.

Concerns about the result were mitigated when the partners reported top-line data showing the efficacy of the vaccine was maintained across different age groups, with 95% in younger adults and 94% in subjects over 65.

The Moderna and Pfizer-BioNTech findings augur well for other mRNA vaccines; their success is also likely good news for a wide swath of COVID-19 vaccines that target the virus’ spike protein.

Still, they have set a high bar, and create a testing ground for mRNA as a vaccine modality to compete with more traditional vaccine formats. If these two vaccines significantly outperform their competitors, there would be a significant impact for future vaccine development, including for future pandemic preparedness.

J&J and AZ are both using viral vector-based vaccines encoding the spike protein.

AZ’s AZD1222 uses a simian adenovirus vector to avoid pre-existing immunity against the vector that would diminish efficacy. J&J’s JNJ-78436735 uses a human adenovirus serotype 26 (Ad26) vector, which is one of the two vectors in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.

So far, J&J is the only company testing a single dose of its vaccine in Phase III; the pharma announced this week that it is starting a second Phase III study testing two doses. The Phase I/II titers and T cell responses the company reported were from a single dose; adding a booster shot should increase them.

Five vaccines could yield pivotal data before the Pfizer-BioNTech and Moderna front-runners become widely available in the U.S. Though that will add more information to help extrapolate from efficacy to antibody titers and cellular responses, it will also make recruitment harder for additional vaccine candidates. 

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