Universal Influenza Virus Vaccines That Target the Conserved Hemagglutinin Stalk and Conserved Sites in the Head Domain

Abstract

Due to limitations of current influenza virus vaccines, new vaccines that mediate broad protection and show high efficacy against seasonal and pandemic viruses are urgently needed. The conserved stalk of the viral hemagglutinin has been identified as potential target antigen for this new generation of vaccines. A vaccination strategy based on chimeric hemagglutinin (cHA), which refocuses the immune response toward the stalk domain and the conserved neuraminidase, is currently being tested in clinical trials. Here we discuss how to improve the cHA antigens to generate vaccine candidates that both induce a broad antistalk response and target conserved immunosubdominant epitopes in the head domain of the hemagglutinin. These novel constructs, termed mosaic hemagglutinins, should provide enhanced protection and should be tested in clinical trials to assess their improved potential as universal influenza virus vaccine candidates.

Asynchrony between virus diversity and antibody selection limits influenza virus evolution

“…In older individuals, multiple previous exposures will eventually lead to preferential activation of recall responses for antibody production to new variants as a result of original antigenic sin (Davenport & Hennessy, 1956), immune backboosting (Fonville et al, 2014), or antigenic seniority (Lessler et al, 2012). Even if the recall responses result in backboosting and higher levels of sIgA, these antibodies are unlikely to be well-matched to the new variant or succeeding variants, as continuous re-exposure favours responses to conserved epitopes (Krammer & Palese, 2019; Krammer, 2019) rather than receptor-binding site epitopes suspected to be most important for immune escape. As a result of the limited ability to generate novel immune responses and the phenomenon of antigenic seniority, an elderly individual who has been exposed multiple times in the past is likely to exert very weak inoculation selection to newly infecting viruses. By contrast, a child recently exposed to influenza virus is more likely to act as a strong selector, due to the availability of mucosal sIgA antibodies and the more limited impact of original antigenic sin.…”

“…Even if the recall responses result in backboosting and higher levels of sIgA, these antibodies are unlikely to be well-matched to the new variant or succeeding variants, as continuous re-exposure favours responses to conserved epitopes (Krammer & Palese, 2019; Krammer, 2019) rather than receptor-binding site epitopes suspected to be most important for immune escape.…”

“…6F,G). Future “universal” influenza vaccines that elicit antibodies targeting the more conserved stalk of the HA protein (Krammer & Palese, 2019) are also unlikely to promote the evolution of vaccine escape mutants at the human population-level. Many HA stalk targeting antibodies have limited capacity to perform initial neutralization of a virus inoculum and instead limit influenza virus infection through antibody dependent cellular cytotoxicity (ADCC), phagocytosis, or complement activation (He et al, 2015).…”

Monoclonal Antibody Responses after Recombinant Hemagglutinin Vaccine versus Subunit Inactivated Influenza Virus Vaccine: a Comparative Study

“…Both vaccine platforms induced low frequencies of stalk-reactive antibodies, likely due to the fact that the stalk is part of a full-length HA in a nonsoluble form (rosettes). Thus, alternative vaccine strategies using recombinant soluble proteins or headless HAs or chimeric HAs with avian exotic heads will be of interest in the quest for a universal influenza virus vaccine based on broadly cross-reactive antibodies (44,45).…”

A comprehensive influenza reporter virus panel for high-throughput deep profiling of neutralizing antibodies

“…Several less broad bnAbs bind to the RBS in the HA head and prevent the virus from engaging sialic acid moieties on the host cell surface, thus exhibiting HAI activity( 12 ). Currently, most universal influenza vaccine candidates aim to induce protective levels of such bnAb response( 11, 13 ). Therefore, comprehensive analysis of the neutralization breadth and potency regardless of HAI activity is critical to accelerate the efforts to develop effective universal influenza vaccines.…”