The rapid identification of a correlate of protection (CoP) for Covid-19 vaccines – based on several harmonized randomized phase 3 trials using validated common tests – constitutes an important achievement in vaccinology. A CoP is an immune marker that can be used to reliably predict how effective a vaccine will be in preventing a clinically relevant outcome. The level of this marker is measured shortly (2-4 weeks) after the completion of the vaccination regimen and provides an actionable basis for decisions such as regulatory approval of an effective vaccine for a new population that has not not been included in pivotal phase 3 randomized trials, or the approval of a refined version of a vaccine that had previously been shown to be effective.
Once established, a CoP can be used as the primary endpoint for interim or full approval of a vaccine for a specific use, if a clinical immuno-bypass study confirms that sufficiently high CoP levels are achieved. For example, the Food and Drug Administration (FDA) extended the approval of the mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) Covid vaccines from older to younger age groups based on a comparison of neutralizing antibody titers. Additionally, FDA guidance and a statement from the European Medicines Agency’s International Coalition of Medicines Regulators recommended that approval of new vaccine strains and booster doses be based on clinical studies of immuno-bypass showing non-inferiority or superiority to a CoP endpoint. Other applications of a CoP include ensuring vaccine consistency from lot to lot, supporting recommendations for co-administration with other vaccines, and determining appropriate expiration dates.
The confusion about CoPs is understandable, given the myriad complex issues associated with their identification and the fact that different uses of CoPs require different validation measures. Evidence that a marker is a CoP generally comes from five main sources: natural history studies that correlate infection-induced immune responses with outcomes; vaccine challenge studies in animals or humans; studies that experimentally manipulate the immune marker to directly assess mechanistic causation (eg, by administering various vaccine doses or using passive antibody transfer); efficacy trials that quantify the relationship between vaccine efficacy and the level of the immune marker in individual vaccine recipients; and meta-analyses of sets of efficacy trials that correlate vaccine efficacy with mean level of immune markers.
Panel A shows the vaccine efficacy observed among participants in five randomized controlled trials of Covid-19 vaccines who tested negative for SARS-CoV-2 at baseline, according to participants’ post-vaccination neutralizing antibody titers for testing. Vaccine efficacy was defined as the percentage reduction in the average risk of Covid-19 in vaccinees, relative to the risk in placebo recipients, and was estimated using a proportional hazards model of Marginalized Cox.1 The data comes from trials of four vaccines: COVE for mRNA-1273,1 SET for Ad26.COV2.S (US study sites only),2 PREVENT-19 for NVX-CoV2373,3 AZD1222 for ChAdOx1 nCoV-19, and COV002 also for ChAdOx1 nCoV-19.4 50% pseudovirus neutralizing antibody titers were measured at day 57 after the first vaccine dose in COVE, AZD1222, and COV002; day 29 at ENSEMBLE (US); and at day 35 in PREVENT-19. Follow-up periods for evaluation of vaccine efficacy ranged from 2 months to 5 months after vaccination. Curves are plotted from the 2.5th percentile to the 97.5th percentile of antibody titer for COVE, ENSEMBLE (US), PREVENT-19, and AZD1222, and over 3 to 140 international units 50% inhibitory dose (IU50) per milliliter for COV002. All analyzes were adjusted for baseline risk score; COVE was also adjusted for coexisting conditions and racial or ethnic origin, and AZD1222 was adjusted for age. Panel B shows histograms (relative frequencies) of neutralizing antibody titers in these assays.
Strong evidence was generated from these five sources for both serum anti-spike IgG concentration and anti-SARS-CoV-2 neutralizing antibody titer as CoP for Covid-19 vaccines. 19 symptomatic; for the sake of brevity, we focus here on the neutralizing antibody titer. Meta-analyses have established high correlations between mean standardized titer and vaccine efficacy, and neutralizing antibody titer has consistently been shown to be a mechanistic CoP in challenge studies in non-human primates. The US government’s COVID-19 Vaccine Correlates of Protection program evaluated CoPs in Phase 3 trials of four vaccines: COVE for mRNA-1273,1 SET for Ad26.COV2.S,2 PREVENT-19 for NVX-CoV2373,3 AZD1222 (US/Chile/Peru) for ChAdOx1 nCoV-19, and COV002 (UK) also for ChAdOx1 nCoV-19.4 Vaccine efficacy always increased markedly with titer (see graphics).
Although we believe the evidence strongly supports the designation of the neutralizing antibody titer as CoP, in recent meetings key opinion leaders have pointed to the absence of CoP. Why does their interpretation of the evidence differ from ours? One of the reasons may be the use of different definitions for a deployable CoP. Often, an immune marker can be used as a CoP because a threshold level can be identified that convincingly discriminates between vaccinees with breakthrough Covid-19 disease and those not infected with SARS-CoV-2. For infections in which viremia is the key to pathogenesis (eg, poliomyelitis), we can identify such a threshold because sufficient levels of antibodies can prevent dissemination of the pathogen into the bloodstream. The same is not true for Covid-19, as it is caused by an infection of the mucous membranes which can be invasive.
Although a CoP threshold is ideal because it can provide an absolute benchmark for approving a vaccine without the need for a comparator vaccine, this goal is likely unattainable for Covid-19, because the amount of virus at which participants to The trial are exposed to vary widely and because CoPs must be able to predict vaccine efficacy over a post-vaccination follow-up period during which antibody levels decline. These factors insert uncontrollable variability into the analysis such that even if neutralizing antibodies were a perfect mechanistic CoP, the titer values in people with Covid-19 would overlap those in people not infected with SARS-CoV-2, as observed in all trials. Yet these partial separations, combined with evidence from the five types of sources defined above, can validate a non-threshold CoP. And such a CoP can be used to predict vaccine efficacy by averaging the estimated vaccine efficacy curve by titer (see graphics) on the distribution of securities.
In phase 3 correlate analyses, researchers investigated the titer of neutralizing antibodies against the original vaccine strain as CoP against Covid-19 caused by circulating strains, which belonged to the original or variant lineages before the emergence of delta (B.1.617.2) and omicron (B.1.1.529). Going forward, CoP definition and validation of the antibody titer for omicron and for future lines will be essential. In ongoing correlation studies on the long-term follow-up of Phase 3 trials, researchers are measuring titers against circulating lines before and after booster doses, enabling these analyses, including determining the need for higher antibody levels for protection against omicron subvariants than for protection against pre-delta viruses. This validation is important given that decisions such as recall recommendations depend on an omicron-specific CoP titer: at its June 28, 2022 meeting, the FDA Vaccine Advisory Board used these titers as key endpoint for comparing vaccine constructs.
Correlates analyzes focused on a single clinical outcome in phase 3 trials: symptomatic Covid-19. This clinical endpoint is appropriate as a basis for decisions. However, CoPs can vary depending on the outcome of interest and therefore should be assessed specifically for distinct endpoints. Ongoing research on correlations supported by the US government for phase 3 trials focuses on the most important outcome: severe Covid-19. If relatively few antibodies are needed to prevent severe disease, these analyzes could set lower bars for approvals based on clinical immunobypass results. While neutralizing antibodies are the mechanistic CoP against infection, other immune responses, including the production of Fc effector antibody functions and T cell functions, play a role in controlling infection if it occurs, and researchers should look for correlates that depend on other immunological functions.
Additionally, anti-mucosal spike IgA was a correlate for prevention of acquisition of omicron infection, as determined by positive viral RNA polymerase chain reaction assay results in triple-vaccinated healthcare workers,5 raising the question of whether mucosal markers are mechanistic CoP and serum titers are non-mechanistic (non-causal) CoP. But although serum titer may not be a mechanistic CoP against the initial acquisition of infection, it is likely such a CoP for endpoints reflecting the presence of invasive disease. In future research, various time points of antibody and T cell measurements should also be investigated.
Binding and neutralizing antibodies have been accepted as CoPs by regulators and have provided very high value for vaccine research, development and use for more than a dozen vaccines against various viral or bacterial diseases . Large studies have generated strong evidence that these antibody markers are CoPs for Covid-19 vaccines – indeed, more evidence than is available for many CoPs for other types of vaccines. The FDA has accepted the neutralizing antibody titer against probable circulating strains as a CoP for several Covid-19 vaccines. Many open questions remain, given that this CoP has been identified in trials involving people who were not previously infected with SARS-CoV-2 and who received spike-only intramuscular vaccines and were subsequently exposed to pre-delta viruses. Nevertheless, while pursuing the next steps – identifying CoPs for new viral variants, for new populations including previously infected people, for new classes of vaccines, and for various aspects of Covid-19 disease (e.g., symptom types, durations, and severity) – we should recognize that neutralizing antibodies are the current CoP for vaccine efficacy, worth using for short-term vaccine decisions.
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