Study shows potential for universal flu vaccine with broad antibody response

A recent study published in the journal Nature Communications observed antibody breadth and effector functions as important immune correlates that can be used to develop universal influenza vaccines. This vaccine could be effective against all influenza virus strains, even those having pandemic potential.

Study: Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children. Image Credit: Africa Studio / Shutterstock

Background

Children are particularly vulnerable to influenza viruses that cause seasonal epidemics and sporadic pandemics. Seasonal influenza epidemics not only lead to an upsurge in hospital admissions but also increase mortality rates in older adults with comorbidities. Many studies have shown that seasonal influenza vaccines provide limited protection against influenza viruses that have the potential to cause a pandemic. However, the 2009 H1N1 pandemic (pH1N1) revealed the effectiveness of seasonal vaccines in protecting children and older adults from the infection. This protection could be due to cross-reactive antibody responses. 

Compared to children, adults possess additional immune correlates, such as T-cell responses and non-neutralizing antibody functions. This is the reason why children require higher concentrations of HAI antibodies for an equivalent amount of immune protection from the infection. To design a next-generation vaccine, it is important to identify immune correlates of protection. In the context of pH1N1 infection, HA-stem-specific antibodies play a crucial role in providing protection, which is mediated by the Fc Receptor (FcR) function. 

Some antibodies that can cross-react between pandemic, seasonal, and avian influenza viruses could reduce the severity of influenza virus infection. In this context, serum antibodies, particularly IgG, can facilitate effector functions, such as directing immune cells to kill infected cells, engulfing infected cells via antibody-dependent phagocytosis (ADCP), and promoting antibody-dependent cellular cytotoxicity (ADCC). These functions are mediated by Fc gamma receptors (FcγR) 3a and FcγR2a.

Mechanistically, FcγR 3a and FcγR2a employ macrophages and natural killer (NK) cells to remove viruses-infected cells. Cross-reaction of ADCC antibodies has been associated with targeting conserved antigenic sites of influenza virus hemagglutinin (HA), the Nucleoprotein (NP), and Matrix 1 (M1).

About the Study

The current study identified several gaps in research regarding antibody effector functions. For instance, few studies have assessed the vaccine-induced ADCC changes, longitudinal durability of vaccine-induced antibody FcR binding and isotype changes, and the alterations in HA-specific antibody responses with vaccination and infection. The currently performed randomized placebo control trial (RCT) investigated the influenza-specific antibody breadth and function of seasonal (S1) H1N1 vaccination and pH1N1 infection.

The antibody features, particularly HAI titer, from seasonal vaccination that could have helped in reducing or delaying contraction of pH1N1 were assessed using selected archived samples. These samples were collected from NCT00792051, a randomized placebo-controlled trial and its follow-up study that used school children between 6 and 17 years old. 

A subset of children who received any influenza vaccination in Year 1 (V1) or not (placebo-V0) was selected for secondary analyses, which helped determine the effectiveness of vaccination against pH1N1 infection.

Study Findings

The current study indicated that non-neutralizing antibodies are highly cross-reactive between different influenza strains and subtypes, which could play an important role in reducing the incidence and severity of infection.

Detecting antibody functions other than HAI is vital to developing next-generation vaccines. This study identified the serological correlates that play an important role in protecting children from pandemic infection. In 2009, when schools were closed for two months, H1N1 transmission was low. However, soon after schools reopened in September 2009, more than 50% of the students were infected within a few months. A very low community uptake of the monovalent pH1N1 vaccine has been documented.

The half-life of different antibody subclasses alters significantly. The current study observed that seasonal vaccination enhances Fc effector functions of pH1N1 specific NP, HA, and neuraminidase (NA) antibodies. However, their function was short-term as it waned off within one year of vaccination. A greater antibody decline was observed in unvaccinated children.

Seasonal vaccination did not boost FcR effector functions to other seasonal-specific antibody responses. Unvaccinated, uninfected children also exhibited increased FcR-mediated effector functions of pandemic-specific NA, HA, and NP antibodies. These children displayed a higher antibody level of NK cell function. pH1 antibodies against H3-HA responses were associated with cross-reactive avian H5-specific IgG, FcγR2a, and FcγR3a responses. This finding implies that cross-reactive responses are less focused and are not trained by seasonal virus exposure of other groups. 

Considering the experimental results, vaccination and prior infection are not associated with the lack of infection in unvaccinated, uninfected children or susceptibility of V1S1 children. More research is required to understand the host factors leading to these outcomes.

Results also indicated that group 2 H3 HA-specific IgG3 antibodies are negative predictors of infection. However, seasonal H1 and pH1-IgG3 antibodies before infection were positively associated and, therefore, protected against infection.

Conclusions

This study shows how universal influenza vaccines, effective against seasonal to pandemic viruses, can be developed. Antibody breadth and FcR effector functions are two important immune correlates that could be exploited to develop this vaccine.