The Moderna mRNA-1273 vaccine was one of the first produced against infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The licensing of this vaccine, like several others, was essential in allowing governments worldwide to begin to dismantle the limitations established to curb coronavirus disease 2019 (COVID-19) transmission.
mRNA vaccines are a relatively new development in vaccination: instead of introducing a protein or a matrix presenting proteins in a pattern for the immune system to recognize and begin producing antibodies against, mRNA vaccines introduce a strand of mRNA to the body, relying on the hosts own cells to produce the protein. This is generally the receptor-binding domain (RBD) on the spike protein in the case of SARS-CoV-2, as this is required for viral cell entrance.
Researchers from Fred Hutchinson Cancer Research Center investigated the vaccination efficacy of the mRNA-1273 vaccine in a paper published in Science.
The researchers looked at the results of 1,010 people who were fully vaccinated and 137 people who were given a placebo. Thirty-four percent of participants were 65 or older, 40% were at risk of a more severe COVID-19, and the participants were relatively evenly distributed across demographic lines. Antibody markers were examined for at least seven days after days 29 and 58, for a total of 116 days after day 29 and 88 days after day 57.
Anti-spike and anti-RBD IgGs were found to be positive in nearly every subject on day 29. ID50 and ID80 titers were found in 82% and 64% of vaccine recipients, respectively. On day 57, nearly everyone who had been vaccinated had a positive antibody response to all four markers. Between the two time points, each marker had a modest correlation. The spike IgG and RBD iGG markers, as well as the ID50 and ID80 markers, were all highly associated, as expected. At each time point, each binding antibody marker was associated with each neutralization marker. In all markers, vaccination breakthrough cases had a smaller mean distribution than non-cases.
To examine the COVID-19 risk following immunization, the researchers utilized a Cox model-based covariate-adjusted COVID-19 incidence for subgroups of vaccine recipients. The multiplicity-adjusted p-values show that vaccine recipients with greater antibody marker levels have a considerably decreased risk, with similar results across all subgroups. Both day 29 and day 57 markers exhibited substantial inverse risk correlations.
Throughout the trial, the cumulative incidence of COVID-19 in vaccinated people was 0.0033. The reverse cumulative distribution function of the ID50 titer, which depicts the incremental change in risk linked with changes in marker levels, was used to construct this cumulative incidence. Specifically, vaccination effectiveness was 51 percent when ID50 was undetectable at day 57. Vaccine effectiveness of 78 percent, 91 percent, and 96 percent was related with Day 57 levels of 10, 100, and 1,000 IU50/mL, respectively. From 10 to 1000 IU50/mL, this meant a 5.5-fold increase in vaccine risk reduction. For day 29 data, vaccine effectiveness estimates increased at similar levels. Binding antibodies yielded results that were similar to neutralizing antibodies.
To make the vaccine efficacy by marker curve flatter, the researchers ran a sensitivity analysis, assuming the presence of an unmeasured confounder related with the antibody marker and COVID-19 outcome. The vaccine efficacy estimates rose with the day 57 ID50 titer, according to this data.
All neutralizing antibodies showed a similar pattern of findings. Estimated vaccination effectiveness observed to vary a very modest amount with each binding antibody marker when unmeasured confounding was considered. Even if confounders had been present, sensitivity analysis based on E-values of vaccination recipient antibody tertile subgroups supported the assumption that vaccine efficacy would have improved with antibody marker level.
The researchers point out that all of the tested binding and neutralizing antibody indicators are inversely associated to the likelihood of SARS-CoV-2 infection. They’re also linked to vaccine efficacy, as one might assume. COVID-19 risk was nearly ten times lower for vaccine recipients who had the top 10% of antibody levels compared to those who had no antibodies detected, based on any antibody marker. Rather than shutting off abruptly at a certain threshold, this risk lowers gradually.
These findings support the notion that neutralizing titer can be utilized as a surrogate marker for COVID-19 vaccination with mRNA-1273. This data could be extremely useful to researchers looking into vaccine efficacy in specific individuals. It could also provide information to immunocompromised and elderly people, as well as clarify how harmful infection persists for at-risk people after immunization.
Gilbert PB. et al., (2021) Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.