Whose immune system is up for another round of SARS-CoV-2?

From Dr. Tomer Hertz, Vaccine and Infectious Disease Division

How do we know if an immune system “power up” is needed to battle the next assault by SARS-CoV-2 variants? Researchers are investigating various arms of the immune system to identify correlates of protection (COPs), or factors associated with reduced infection rates, disease severity and/or mortality. Studies have highlighted IgG neutralizing antibodies that bind and “neutralize” infectious virus and cellular responses as COPs. To identify new correlates, Dr. Tomer Hertz, formerly of the Vaccine and Infectious Disease Division at Fred Hutch, and colleagues evaluated antibody-based immune responses from people who received three versus four doses of the Pfizer-BioNTech vaccine during the time that the Omicron BA.1 variant was circulating (January-February 2022). They found that a fourth vaccine dose induced increased IgG and IgA antibodies and in general, heightened IgG and IgA levels were associated with reduced symptomatic SARS-CoV-2 infection. Their findings were published in Nature Communications.

To identify correlates of protection, the researchers performed antibody baseline analyses on blood samples taken over a 3-month duration from ~600 individuals of 18 years of age or older. About 240 individuals received four vaccine doses and of these, 30% became infected, while ~360 individuals received three vaccine doses, and 45% of this group became infected. To test antibody neutralization, the researchers used parts of the spike protein from each of the following SARS-CoV-2 variants of concern (VOCs): Alpha, Beta, Wuhan, Delta, Gamma, Iota, Kappa, Mu, Theta and several spike point mutants from the Wuhan VOC. “Previous studies of binding antibody COPs were based on ELISA titers to a single viral variant, requiring one to choose a relevant variant,” state the researchers. Intriguingly, the researchers found that in their cohort, low IgG and IgA antibody baselines to the spectrum of tested spike antigens correlated with higher rates of symptomatic SARS-CoV-2 infections. They also noted that combined low IgG and IgA had stronger correlations with symptomatic infections than either IgG or IgA alone. These findings support the use of combined IgG and IgA neutralization analyses for various spike antigens instead of selecting a single antigen to predict immune responsiveness to infection by SARS-CoV-2 variants.

The researchers next investigated whether the fourth vaccine dose was able to boost these low levels of broad spike-targeting IgG and IgA neutralizing antibodies. At 30 days following the fourth vaccination dose, about 35% of vaccinated individuals still had low levels of neutralizing antibodies. However, the researchers stated that “the majority of participants (65%) generated a significant rise in neutralizing antibody titers at day 30, demonstrating their ability to mount an adequate immune response following a fourth booster dose. In fact, on day 30, we found no significant differences between the individuals in the low-baseline and high-baseline groups, indicating that the fourth dose induced steeper rises in neutralizing antibody titers in the low-baseline group.” These findings support the use of additional vaccine doses for people with low baselines of neutralizing antibodies.

The incidence of symptomatic infection increases at a greater rate for individuals with lower IgG and IgA antibodies to spike mutants and VOCs. Individuals who received four vaccine doses as opposed to three doses have lower cumulative rates of symptomatic infection.
The incidence of symptomatic infection increases at a greater rate for individuals with lower IgG and IgA antibodies to spike mutants and VOCs. Individuals who received four vaccine doses as opposed to three doses have lower cumulative rates of symptomatic infection. Figure from primary manuscript

This approach of evaluating IgG and IgA neutralizing antibodies to a range of SARS-CoV-2 variant spike proteins was also applied to a second cohort of individuals with initial and subsequent blood samples collected over a 9-month period. In this second study, 72% of the 46 individuals became infected with SARS-CoV-2. These individuals had received either 2 or 3 doses of the Pfizer BNT162b2 vaccine. Yet again, combined IgG and IgA neutralizing antibody levels were correlated with protection. These findings highlight the use of IgA in addition to previously noted IgG neutralizing antibodies as COPs by evaluating their binding affinity to a spectrum of spike variants instead of a single spike version.

“Due to the rapid evolution of SARS-CoV-2, it is difficult to identify the optimal single marker or variant which may best predict protection from infection for a novel VOC,” state the researchers. “Our data suggest that by using aggregate cross-reactivity measures to multiple variants, we can obtain more robust COPs even for strains that are antigenically distinct from previous strains, such as the Omicron B.A1 strain 7.” Regardless of the number of vaccine doses received, heightened IgG and IgA antibody levels were found to be COPs against infection. It is unclear why a subset of individuals did not have increased neutralizing antibodies following the fourth vaccine dose. The researchers add that “additional studies are required to assess whether this subpopulation is also at an increased risk for severe disease, and whether it may spread infection more readily than others.”

The spotlighted research was funded by the Clalit Health Services and the Clinical Research Center at the Soroka University Medical Center, the Israel Science Foundation (ISF), the Israeli Ministry of Science and Technology, the Israel Science Foundation, the Ben-Gurion University of the Negev COVID-19 Research Task Force, the National Institutes of Health, and Department of Health and Human Services.

Hertz T, Levy S, Ostrovsky D, Oppenheimer H, Zismanov S, Kuzmina A, Friedman LM, Trifkovic S, Brice D, Chun-Yang L, Cohen-Lavi L, Shemer-Avni Y, Cohen-Lahav M, Amichay D, Keren-Naus A, Voloshin O, Weber G, Najjar-Debbiny R, Chazan B, McGargill MA, Webby R, Chowers M, Novack L, Novack V, Taube R, Nesher L, Weinstein O. 2023. Correlates of protection for booster doses of the SARS-CoV-2 vaccine BNT162b2. Nat Commun. 14(1):4575.