A win for vaccines: immune correlates identified for COVID-19

From the Fong, Gilbert, and collaborating labs, Vaccine and Infectious Disease Division & Public Health Sciences Division

Recently, scientists at the Hutch and around the world celebrated an important milestone in the fight against COVID-19: the identification of antibodies as correlates of protection for COVID-19 vaccines.

Correlates of protection, or immune correlates, are responses to a vaccine that predict how well a vaccinated person will be protected from future infections. Each disease has its own set of unique immune correlates: knowing these correlates for a particular disease is an important step towards the creation of effective vaccines.

In a recent study published in Nature Communications, a team of scientists demonstrated evidence for three antibody markers as correlates of protection for COVID-19. Several scientists from the Fred Hutchinson Cancer Center were involved in the study, including lead author Dr. Youyi Fong and senior author Dr. Peter Gilbert, both professors in the Vaccine and Infectious Disease and Public Health Sciences Divisions.

The concentration, or titer, of two types of antibody measurements is often implicated in determining correlates of protection for vaccines: binding antibodies and neutralizing antibodies. Binding antibodies are produced at high levels. They recognize the virus and bind to it, but are unable to directly protect against viral infection. Binding antibodies alert other components of the immune system to the presence of the virus.  On the other hand, neutralizing antibodies effectively defend the cell from the virus by preventing the virus from getting into cells; in other words, they ‘neutralize’ the threat posed by the virus.

In 2021, The US Government COVID-19 Response Team partnered with COVID vaccine developers to design and carry out COVID-19 vaccine efficacy trials. An important goal of these trials was to identify correlates of protection for COVID based on both binding and neutralizing antibody titers.

Dr. Fong explained that by analyzing the data from these efficacy trials, researchers had previously identified the level of antibodies elicited by mRNA and adenoviral-vectored COVID vaccines as correlates of protection. (Both Pfizer-BioNTech and Moderna are mRNA COVID vaccines, whereas Johnson & Johnson’s Janssen COVID vaccine is adenoviral vectored.)

For the mRNA and adenoviral-vectored COVID vaccines, the analyses identified three specific antibody markers as correlates of protection: anti-spike binding IgG concentration, anti-RBD binding IgG concentration, and pseudovirus 50% neutralizing antibody titer.  Spike is the protein displayed on the surface of the virus particle that the virus uses to infect cells. RBD, or Receptor-Binding Domain, is the precise fragment of spike that attaches to human cells.

Left: graph depicting the relationship between vaccine efficacy (y axis) and the neutralizing antibodies elicited by the vaccine (x axis). Right: histograms showing the relationship between vaccine efficacy (y axis) and the neutralizing antibody titer (x axis) for different COVID-19 vaccines.
Levels of neutralizing antibodies elicited from different COVID-19 vaccines are correlated with vaccine efficacy. Images provided by Dr. Youyi Fong.

In the present study, Dr. Fong and colleagues looked for immune correlates for a recombinant-protein COVID vaccine: the NVX-CoV2373 SARS-CoV-2 vaccine, colloquially known as Novavax. The efficacy trial for this vaccine, called PREVENT-19 (a jazzy acronym for Prefusion Protein Subunit Vaccine Efficacy Novavax Trial – COVID-19), took place in the United States and Mexico in the winter of 2020-221. Two-thirds of the nearly 30,000 participants received two doses of the vaccine, and the other third received placebo shots. The trial had showed that those who received the Novavax vaccine were at 90% lower risk of developing COVID-19 compared to those who had received the placebo shot.

Remarkably, researchers found that the three antibody markers identified as correlates of protection in the mRNA and adenoviral-vectored COVID vaccines were also “inversely associated with COVID-19 risk and directly associated with vaccine efficacy” for the recombinant-protein Novavax vaccine. In spite of the fact that the three vaccines use totally different strategies to train the immune system to fight off the SARS-CoV-2 virus, the observation that the levels of antibodies elicited are reliable correlates of protection is, as Dr. Gilbert and colleagues noted in a recent article, a “COVID-19 milestone.” The validation of these measures as correlates of protection for COVID-19 will likely facilitate the approval and wider use of vaccines.

“The third replication [with a recombinant-protein COVID vaccine] of such a finding reinforces the notion that the level of antibodies elicited by a COVID vaccine may be a valuable tool for speeding up vaccine approval,” said Dr. Fong. This is particularly important for expanding vaccine access to populations not represented in initial clinical trials, including children.

Identification of correlates of protection would also expedite approval for alternative vaccine formulations and dosing schedules that are more effective against the virus, a particularly relevant concern for a rapidly evolving virus like SARS-CoV-2. “Future work will leverage additional samples from the PREVENT-19 trial to study immune correlates of Delta-COVID,” said Dr. Fong. “More broadly, we will also work on using samples from other USG-supported trials to study antibody immune correlates for Omicron-COVID.”

Dr. Gilbert agrees that identifying immune correlates for variants is a priority in the fight against COVID: “These data will allow us to build a model for using antibody levels to predict the level of vaccine efficacy to prevent COVID with new viral strains.”

This work was supported by Novavax; the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA); the National Institute of Allergy and Infectious Diseases; and the National Institutes of Health.

The Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Lawrence Corey, Peter Gilbert, and James Kublin contributed to this work.

Fong Y, Huang Y, Benkeser D, Carpp LN, Áñez G, Woo W, McGarry A, Dunkle LM, Cho I, Houchens CR, Martins K, Jayashankar L, Castellino F, Petropoulos CJ, Leith A, Haugaard D, Webb B, Lu Y, Yu C, Borate B, van der Laan LWP, Hejazi NS, Randhawa AK, Andrasik MP, Kublin JG, Hutter J, Keshtkar-Jahromi M, Beresnev TH, Corey L, Neuzil KM, Follmann D, Ake JA, Gay CL, Kotloff KL, Koup RA, Donis RO, Gilbert PB; Immune Assays Team; Coronavirus Vaccine Prevention Network (CoVPN)/2019nCoV-301 Principal Investigators and Study Team; United States Government (USG)/CoVPN Biostatistics Team. 2023. Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial. Nature Communications. 14(1):331.