Influenza vaccine: progress in a vaccine that elicits a broad immune response

ABSTRACT

Introduction:

The licensed seasonal influenza vaccines predominantly induce neutralizing antibodies against immunodominant hypervariable epitopes of viral surface proteins, with limited protection against antigenically distant influenza viruses. Strategies have been developed to improve vaccines’ performance in terms of broadly reactive and long-lasting immune response induction.

Areas covered:

We have summarized the advancements in the development of cross-protective influenza vaccines and discussed the challenges in evaluating them in preclinical and clinical trials. Here, the literature regarding the current stage of development of universal influenza vaccine candidates was reviewed

Expert opinion:

Although various strategies aim to redirect adaptive immune responses from variable immunodominant to immunosubdominant antigens, more conserved epitopes are being investigated. Approaches that improve antibody responses to conserved B cell epitopes have increased the protective efficacy of vaccines within a subtype or phylogenetic group of influenza viruses. Vaccines that elicit significant levels of T cells recognizing highly conserved viral epitopes possess a high cross-protective potential and may cover most circulating influenza viruses. However, the development of T cell-based universal influenza vaccines is challenging owing to the diversity of MHCs in the population, unpredictable degree of immunodominance, lack of adequate animal models, and difficulty in establishing T cell immunity in humans.

ABBREVIATIONS

cHA: chimeric HA; HBc: hepatitis B virus core protein; HA: hemagglutinin; HLA: human leucocyte antigen; IIV: inactivated influenza vaccine; KLH: keyhole limpet hemocyanin; LAH: long alpha helix; LAIV: live attenuated influenza vaccine; M2e: extracellular domain of matrix 2 protein; MHC: major histocompatibility complex; mRNA: messenger ribonucleic acid; NA: neuraminidase; NS1: non-structural protein 1; qNIV: quadrivalent nanoparticle influenza vaccine; T_RM: tissue-resident memory T cells; VE: vaccine effectiveness; VLP: virus-like particles; VSV: vesicular stomatitis virus

KEYWORDS:

• Vaccine
• influenza
• MHC
• antigen
• conserved epitopes
• universal influenza vaccine

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer has disclosed that they have a pending grant with Sanofi Pasteur on currently licensed vaccine. Peer reviewers in this manuscript have no other relevant financial or other relationships to disclose.

Article highlights

• Influenza remains a serious public health problem due to the high antigenic variability and viral ability to escape the immunity established after previous infections or vaccinations.

• Currently licensed influenza vaccines predominantly induce neutralizing antibodies targeted at hypervariable epitopes, requiring an almost annual update on the composition of seasonal influenza vaccines.

• The performance of existing vaccines can be improved by adding potent adjuvants and the use of substrates for production other than chicken embryos; however, these approaches do not significantly increase the breath of induced antibody responses.

• In the past decade, substantial progress has been made in developing more broadly protective influenza vaccines that target conserved viral antigens, such as HA stalk domain, NA, or M2e; in addition, T cell-based approaches have been developed.

• T cell-based vaccines have the highest potential to induce long-lasting cross-protective memory responses; however, the development of these vaccines is accompanied by major challenges, such as the high diversity of MHCs in the population and lack of adequate animal models.

• There are critical problems with identifying immunological endpoints that can be used as criteria for licensing new vaccines for humans; finding real-life correlates of protection for each vaccine platform is challenging, and more research is needed to address these issues.

Supplemental data

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the Russian Science Foundation under Grant 21-75-30003 and by the Russian Federation President grant MD-327.2020.7.