A Complex Dance: Measuring the Multidimensional Worlds of Influenza Virus Evolution and Anti-Influenza Immune Responses

Abstract

The human antibody response to influenza virus infection or vaccination is as complicated as it is essential for protection against flu. The constant antigenic changes of the virus to escape human herd immunity hinder the yearly selection of vaccine strains since it is hard to predict which virus strains will circulate for the coming flu season. A “universal” influenza vaccine that could induce broad cross-influenza subtype protection would help to address this issue. However, the human antibody response is intricate and often obscure, with factors such as antigenic seniority or original antigenic sin (OAS), and back-boosting ensuring that each person mounts a unique immune response to infection or vaccination with any new influenza virus strain. Notably, the effects of existing antibodies on cross-protective immunity after repeated vaccinations are unclear. More research is needed to characterize the mechanisms at play, but traditional assays such as hemagglutinin inhibition (HAI) and microneutralization (MN) are excessively limited in scope and too resource-intensive to effectively meet this challenge. In the past ten years, new multiple dimensional assays (MDAs) have been developed to help overcome these problems by simultaneously measuring antibodies against a large panel of influenza hemagglutinin (HA) proteins with a minimal amount of sample in a high throughput way. MDAs will likely be a powerful tool for accelerating the study of the humoral immune response to influenza vaccination and the development of a universal influenza vaccine.

Cross-reactive anti-hemagglutinin (HA) IgG responses are shaped by previous long-interval monovalent H5 vaccination and highly correlated with HA antigenic distance

“…Two major impediments to universal flu vaccine development are the constant antigenic changes of influenza strains, and that the human antibody response is shaped by prior influenza exposure history (39). In addition, vaccination strategies for emergent influenza strains need to take into account both the vaccination schedule, and the ability of HA imprinting to can hinder immune responses to new antigens.…”

“…edit distance, Damerau-Levenshtein distance). Experimentally it can be derived by calculating the n-dimensional distance between immune reactivity of sera from a subject vaccinated with a single virus against a panel of other HAs from disparate influenza strains (39). As we have previously shown (37), the smaller the antigenic distance between the prime and boost HAs, the stronger the post-boost vaccination increase in vaccine speci1c anti-HA IgG levels.…”

The potential for antibody-dependent enhancement of SARS-CoV-2 infection: Translational implications for vaccine development

“…Vaccine-specific variations in ADE could occur for many reasons, including differences in vaccine adjuvant, vaccine protein glycosylation, and prior exposure to other CoV strains. Multiplex methods developed for influenza can be quickly adapted to this use [20], especially to assess the balance between vaccine-induced protection from infection versus increased risk of severe disease with subsequent infection despite vaccination. Further clinical studies will be needed to assess this risk in both vaccinated and infected individuals.…”

Measuring the Serologic Response to Severe Acute Respiratory Syndrome Coronavirus 2

“…All have previously been used to detect antibodies to other viral pathogens. 45 In general, these methods involve solid phase coupling of recombinant S or NP as fully trimerized (S protein), monomeric (NP), or peptide fragments (S1-RBD, linear peptide fragments). The solid phase coupled proteins are incubated with serum to allow immunoglobulin binding, which is detected by a secondary anti-IgG/IgA/IgM reagent.…”