This article was co-written with Austin Henley and Emily Bosarge, 2019 PharmD Candidates, Harrison School of Pharmacy, Auburn University.

Influenza is a disease that has historically had significant issues with prevention and treatment. Currently, the flu vaccine is the only vaccination that requires annual administration. This is due to the innate characteristics of the influenza virus, which exhibits strong antigenic drift and is constantly mutating. The virus can look different every year causing patients to no longer be protected.1 Subsequently, influenza can have a profound health burden; for example in the United States there were 810,000 hospitalizations, and 61,000 flu-related deaths during the 2017-2018 flu season.2

The World Health Organization (WHO) and the CDC have task forces that investigate and project what strains will be newly evolving for the upcoming year. For the 2019-2020 season, the vaccine strains were updated to cover different variants of the H3N2 and H1N1 lineage viruses.2 In order to change this, research has been conducted to produce a vaccination that gives patients long-lasting protection from influenza.3

To create such a vaccine, the inherent characteristics of the constantly mutating influenza virus must be overcome.4 To this end, National Institute of Health (NIH) has developed 4 goals for the development of a “universal” flu vaccine. A successful “universal” vaccine should: be at least 75% effective, protect against group I and II influenza A viruses, have durable protection that lasts at least 1 year, and be suitable for all age groups.3 In order to reach these goals for development, research is being conducted on multiple fronts.

Research has begun with identifying targets that are common to all influenza virus strains regardless of mutations. The most promising candidate is currently Multimeric-001 (M-001) which is made up of 9 different peptides that are copies of assorted viral proteins, including HA’s that are conserved between Influenza A and B strains.5 In 2012, the first in-human phase I/II clinical trial of M-001 was published.6 The single-center, randomized, placebo controlled, single-blind study evaluated the safety and tolerability of M-001 in 60 healthy adults ages 18-49 years in Israel.6

The study found M-001 to be safe and well-tolerated. Of the reported adverse events, 88.6% were mild and occurred within 72 hours of vaccination. Of the adverse events that occurred, none could be tied to a specific dose or formulation. As for efficacy, there was a 50-fold increase in post immunization antibody titer following Adj M500 (p≤0.05) and a 37-fold increase in anti-Multimeric-001 IgG titers following the Adj M250 vaccination (p≤0.05).⁶

Currently, a phase III, placebo-controlled, randomized clinical trial is underway, and it is expected to be complete by May 2020.5 The objective of this trial is to assess the safety and clinical efficacy of M-001 as a standalone universal flu vaccine. M-001 is administered as 2 doses separated by 21 days. The investigators intend to enroll more than 9600 patients age 50 years and older, and follow them for up to 2 flu seasons. If this trial has positive results, it may significantly change how people view the influenza vaccine.
 
In addition, there are 2 other universal flu vaccines under investigation. One study is evaluating a prime-boost regimen of a chimeric HA universal flu vaccine in the United States. It is a multi-center, randomized, controlled, observer-blind, phase 1 trial in which participants will initially receive either a live attenuated influenza vaccine (LAIV), inactivated influenza vaccine (IIV) ± adjuvant, or placebo, followed by IIV ± adjuvant, or placebo 3 months later.5

A second trial is studying a universal flu vaccine (Uniflu) composed of recombinant protein HBc-4M2eh in Russia. The trial for Uniflu is a single-site, randomized, double-blind, placebo-controlled, phase 1 study.5 Participants received 2 doses of Uniflu separated by 21 days and received high-dose Uniflu, low-dose Uniflu, or placebo.5 In animal studies, there have been 2 promising strategies for the further development of a universal vaccine. The first strategy utilized the protein ferritin as an important component that can self-assemble into nanoparticles.3 The other strategy combined 4 subtypes of the H protein, and it is made from noninfectious virus-like particles.3 Though these products have a long way to go before they are available for use in clinical practice, the results of these studies will hopefully move us closer to a more effective option for influenza prevention.

In the past, the flu vaccine has garnered a bad reputation amongst the public due to its apparent poor efficacy related to overcoming the innate characteristics of the influenza virus. The implications of a universal flu vaccine that can protect against this virus regardless of strain are far reaching.

Though there are still questions about whether these investigational flu vaccines will be impervious to mutation and genetic drift, the results of the research on them provide hope that we could see a true universal flu vaccine in the near future.


REFERENCES
  1. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A pathophysiologic approach. 10th ed. [AU Intranet; Access Pharmacy] New York: McGraw Hill Medical; ©2017 [cited 2019 Nov 15]. Chapter 109. Available from: https://accesspharmacy.mhmedical.com/book.aspx?bookid=1861#130942133
  2. CDC – National Center for Health Statistics – Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths in the United States — 2017–2018 influenza season. https://www.cdc.gov/nchs/. [cited 2019 Nov 15].
  3.  Universal Influenza Vaccine Research. The National Institute of Allergy and Infectious Diseases. https://www.niaid.nih.gov/diseases-conditions/universal-influenza-vaccine-research. [cited 2019 Nov 15].
  4. Sautto, G. A., Kirchenbaum, G. A., & Ross, T. M. (2018). Towards a universal influenza vaccine: different approaches for one goal. Virology journal, 15(1), 17. doi:10.1186/s12985-017-0918-y
  5. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). [cited Nov 15, 2019] accessed from: https://clinicaltrials.gov/ct2/results?cond=universal+influenza+vaccine&term=&cntry=&state=&city=&dist=
  6. Atsmon J, Kate-Ilovitz E, Shaikevich D, et al. Safety and Immunogenicity of Multimeric-001-a Novel Universal Influenza Vaccine. J Clin Immunol (2012)32:595-603. https://doi.org/10.1007/s10875-011-9632-5