Influenza Virus Evolution: Challenges of Antigenic Drift and Shift in Vaccine Design and Response

 Introduction

The underlying principles of influenza vaccination have not altered significantly over 70 years. The greatest challenge lies in the virus continuously evolving by antigenic drift and shift, reducing the efficacy of the vaccine and requiring ongoing revision. Currently, available vaccines rely on the tactic of attacking specific viral proteins, which are too few to defend against all the strains.

Developing effective vaccines for influenza is complicated due to the virus’s propensity to mutate frequently, especially in the hemagglutinin (HA) protein. Even though antibodies to the HA head are known to neutralize infection, this region is highly variable, and therefore, vaccines are not very effective in the long term. Thus, vaccines currently in use offer temporary protection and must be updated annually. Influenza A and B viruses continue to cause severe disease across the globe, and evolution is tracked by the WHO for vaccine composition. Although this system enables a response to viral change, it is imperfect. New approaches to induce broader immunity and improve vaccine design are explored, but consensus on the best path is still evolving.

Antigenic Shift and Antigenic Drift in the Context of Influenza

Influenza viruses are unstable pathogens that have a high degree of mutation and evolve rapidly by two mechanisms: antigenic drift and antigenic shift. Antigenic drift is a progressive mutation of viral genes, more specifically hemagglutinin (HA) and neuraminidase (NA), owing to the viral error-prone RNA polymerase. The mutations alter surface epitopes, which allow the virus to evade host immunity and cause the recurring emergence of new seasonal strains. Drift is a continuous process and can reduce the effectiveness of existing vaccines, rendering annual revaccination essential. (Kim et al., 2018)

Antigenic shift, on the other hand, is a sudden genetic reassortment that creates entirely new influenza. A subtype by gene segment exchange, often between human and animal strains. Such an exchange has the potential to create pandemics, as happened in the 1918 Spanish Flu (H1N1), which originated from an avian source, killing ~50 million people.1957 Asian Flu (H2N2) – result of reassortment between human and avian strains. 1968 Hong Kong Flu (H3N2) – another reassortment involving avian genes. 2009 Swine Flu (H1N1) – a mix of swine, avian, and human influenza viruses. Reassortment occurs only in influenza A viruses due to their immense animal reservoirs; influenza B viruses, without any significant animal reservoir, fail to reassort.
 The segmented nature of the influenza genome permits reassortment to occur on co-infection, leading to numerous genetic combinations. While none of them may be viable, some reassortants are used for vaccine manufacturing. Vaccine production utilizes reassortant “seed viruses” with target HA/NA genes combined with master strains optimized for highest yield and safety. Reverse genetics has subsequently further optimized the process to more accurately manipulate genes to enhance vaccine production. Nevertheless, with or without the improvement, influenza virus variability continues to be an issue for timely vaccine matching and indicates the need for better strain prediction and more comprehensive immune responses.

Challenges and Limitations of Current Influenza Vaccines

Commercial influenza vaccines are either inactivated, recombinant, or live attenuated. Recombinant and inactivated vaccines are mostly administered intramuscularly, while live attenuated vaccines are intranasal. Although they have been available since 1945, the vaccines have limitations, especially among the elderly, with efficacy dipping below 50%. Although they can decrease illness by 70-95% in healthy adults, this usually fails to generalize across populations, which fuels public disbelief.

One of the largest obstacles in improving vaccine effectiveness is that there are not good immunologic correlates other than hemagglutination inhibition (HI) titers. Live attenuated vaccines, for instance, work well without crossing these HI levels and therefore suggest the existence of other immune processes. Egg-based production is also a bottleneck because it can introduce unwanted mutations in viral replication and affect antigen match. While recombinant and cell-based systems like the baculovirus system are promising and have proven to be feasible, they are limited by cost, lower yields, and the requirement for infrastructure. (Kim et al., 2018)

How can the current vaccines be improved?

Enhancing current systems has included adding neuraminidase (NA) antigens to augment immunoprotection, as NA antibody presence is in correlation with reduced disease and infection severity. NA vaccine formulations are diverse and uncontrolled, however. Efforts to enhance vaccine antigenicity by using adjuvants like AS03, MF59, and AF03 for promoting immune responses and lowering vaccine doses are ongoing. Other investigational adjuvants, including ISCOMATRIX and virosomes, are also being explored, but the issue of repeated booster dosages and regulatory hurdles persists.

To advance towards a global influenza vaccine, researchers are turning their attention to more conserved viral components, namely the HA (hemagglutinin) stalk, M2e (matrix 2 ectodomain), and NP (nucleoprotein). M2e-based vaccines have produced cross-protection in animal models but, as yet, not optimally in humans. Strategies for the induction CD8+ T cell immunity are also being explored because T cells are capable of recognizing internal conserved proteins and can provide heterologous protection, but evidence of utility in humans is yet to be established.
 Another area of promise is inducing widely neutralizing antibodies to the HA stalk domain.

     

Figure: HA as a vaccine target. Representation of HA trimer showing the two major domains (globular head and stalk) and their antigenic and immunologic characteristics.

These antibodies are less dominant than those to the globular head but are capable of cross-reacting with multiple influenza strains. Single B cell and reverse genetics technologies have enabled the identification of extremely potent stalk-specific antibodies (e.g., CT149, MEDI8852). Computational consensus antigens are also being engineered to minimize genetic distance from circulating strains to improve match and breadth. Although most efforts are focused on influenza A due to its variability and pandemic potential, universal influenza B vaccines are also in the works, some targeting conserved cleavage sites in the HA stalk. Cross-lineage protection has been shown in mouse studies.
 

 Conclusion

A universal flu vaccine remains an aspiration, but a more practical goal is extending the life of available vaccines and protecting against more viruses. Among the biggest challenges are how to target stable areas of the virus and how to augment responses in older people. Future research on stronger, more widespread protection is ahead despite eroding public confidence based on patchy performance. (Kim et al., 2018)

References:

Kim, H., Webster, R. G., & Webby, R. J. (2018). Influenza Virus: Dealing with a Drifting and Shifting Pathogen. Viral Immunology, 31(2), 174–183. https://doi.org/10.1089/vim.2017.0141