Overcoming Challenges to Create a Universal Influenza Vaccine
An ideal vaccine would induce an immune response against the part of the flu virus HA that remains conserved from isolate to isolate and from strain to strain.
Influenza is a significant cause of global morbidity and mortality due to viral infections. The Centers for Disease Control and Prevention (CDC) estimated the number of influenza-associated deaths in the United States to range between 12,000 (low) and 56,000 (high) in the period between the 2010/2011 and 2013/2014 influenza seasons.1 According to the World Health Organization (WHO), inter-pandemic influenza causes between 3 and 5 million cases of severe illness and between 250,000 and 500,000 deaths globally each year.2
Although influenza vaccines offer the best available protection against seasonal and pandemic influenza strains,3 they are not perfect. The hemagglutinin (HA) protein — the main antigen of the influenza virus — is characterized by a high level of plasticity and the ability to rapidly acquire mutations,4 causing antigenic drift and a need for regular updates to the vaccine.5
With the aim of overcoming the shortcomings of currently available influenza vaccines, researchers led by experts from the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) embarked on a quest to develop a universal influenza vaccine (UIV). On June 28-29, 2017, NIAID convened a workshop entitled “Pathway to a Universal Influence Vaccine,” which summoned approximately 150 experts and clinicians from the United States and abroad.6 In a post-meeting report, a reasonable target for UIV was defined as “a vaccine with ³75% protection against symptomatic disease caused by group 1 and group 2 influenza A viruses lasting ³12 months in all populations.”6
Infectious Disease Advisor discussed the latest progress on UIV research with Anthony S. Fauci, MD, director of NIAID at NIH in Bethesda, Maryland, and Florian Krammer, PhD, associate professor in the department of microbiology at Icahn School of Medicine at Mount Sinai in New York.
Infectious Disease Advisor: What is the main goal of a UIV? Which shortcomings of currently available influenza vaccines is an effective UIV aiming to overcome?
Anthony S. Fauci, MD: The main goal of a UIV is to provide protection against multiple strains of influenza. The influenza viruses that we experience each year change slightly from year to year, necessitating a change in the vaccine almost invariably from year to year. The part that generally changes is a component — the head — of the hemagglutinin (HA) molecule and that is the part of the HA against which we are aiming to achieve a protective immune response. When this component changes and the vaccine does not match that change, the vaccine works poorly.
An ideal UIV would induce an immune response against that part of the influenza virus HA that remains conserved from isolate to isolate and from strain to strain — the stem. The shortcoming of the currently available influenza vaccines is that they must be updated almost every year to keep up with the inevitable changes (drifts) in the virus. Also, when the virus changes dramatically (shifts), then you have a strain capable of causing a pandemic.
Infectious Disease Advisor: How much progress has been made in development of a UIV in the recent years?
Dr Fauci: Considerable progress has been made toward developing a UIV. The part of the HA molecule that does not change from isolate to isolate — the stem — has been identified and characterized at the atomic level. Preclinical studies of a number of vaccine candidates have begun in animal models and early phase 1 trials of candidate UIVs have begun in humans. Having said this, we have a long way to go to develop a truly universal vaccine and this process will take several years.
Infectious Disease Advisor: Are any promising UIV candidates currently being tested in human clinical trials?
Dr Fauci: HAs in a nanoparticle platform; a multiple peptide prime plus an inactivated influenza virus boost (BiondVax): a DNA prime plus an inactivated influenza virus boost; a live attenuated vaccine prime followed by an inactivated vaccine boost, among others, have already entered into phase 1 clinical trials for safety and immunogenicity.
Infectious Disease Advisor: What are some of the challenges associated with UIV development and what is the research community doing to address them?
Dr Fauci: There are a number of challenges, all in the realm of scientific discovery. Can the body actually make a predominant immune response against the stem of HA and not be diverted to a response against the immunodominant head of HA? We are just beginning to appreciate the fact that a person's first experience with influenza, by vaccine or infection, plays a significant role in how one responds to subsequent infections and vaccines. This is referred to as “imprinting” or “original antigenic sin.” Also, UIVs may be variably effective depending heavily on the age at which an individual had prior experiences with influenza. In addition, the durability of response is critical: how many times over one's lifetime must you vaccinate with a UIV? Every 5 years? Every 10 years? Will we need to separate UIVs for all the group 1 influenzas and the group 2 influenzas? These are all unknowns right now.
Infectious Disease Advisor: Can you briefly describe the main targets for a universal influenza vaccine?
Florian Krammer, PhD: Universal influenza virus vaccines need to target the conserved parts of the virus that do not change much over time. Currently, the conserved stem domain of the HA is the main target. Others include M2e, the small ectodomain of a viral ion channel called M2, the neuraminidase, and internal proteins like the nucleoprotein.
Vaccines that target the conserved stem domain are currently being tested in clinical trials. For those, the main mode of action has not been completely elucidated yet, but it is likely a combination of broad virus neutralization and Fc-based effector functions (eg, antibody-dependent killing of infected cells through NK cells or macrophages).
Infectious Disease Advisor: What are some of the ways in which the introduction of an effective UIV might change influenza prevention efforts?
Dr Krammer: A universal influenza virus vaccine would be a game changer that would have a significant impact on public health. A vaccine that has to be given only 2 to 3 times in a lifetime will be much better accepted than a vaccine that has to be given every year, so it is likely that vaccination rates would reach a very high level. In addition, the current vaccines are not included in childhood vaccination programs in low and middle income countries (LMICs), because it is too expensive and complicated to give them every year. A universal vaccine that has to be given only 2 times in a lifetime could be incorporated into these vaccination programs meaning that the influenza vaccine would suddenly become accessible to LMICs. This would also enhance our pandemic preparedness. Finally, a high vaccination rate with a universal influenza virus vaccine might actually in the end eradicate influenza B. Unlike influenza A viruses, which have an extensive animal reservoir, influenza B viruses almost exclusively circulate in humans and can therefore be eradicated (if the vaccine is good enough and the vaccination rate is high enough).
Infectious Disease Advisor: From your perspective as a researcher, how close is the medical research community from having an effective UIV available for distribution worldwide?
Dr Krammer: I would say it will take approximately 10 years for the first candidates to be on the market. But it is more complicated than that. While we can show that a universal influenza virus vaccine protects animals against all types of influenza, we can only show protection against H1N1, H3N2 and influenza B in humans, simply because the other subtypes do not circulate in humans right now. It will, therefore, be difficult from a regulatory perspective to get a vaccine label that says “universal influenza virus vaccine.” Even if the vaccine protects universally, this can't be claimed until it has been demonstrated in humans. And that will take a long time. But yes, I think 10 years is a realistic time frame to get one of these vaccines on the market.
- Estimating seasonal influenza-associated deaths in the United States. Centers for Disease Control and Prevention (CDC) website. Updated December 9, 2016. www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm. Accessed December 8, 2017.
- Influenza. World Health Organization. www.who.int/immunization/topics/influenza/en/. Updated January 25, 2008. Accessed December 8, 2017.
- Nachbagauer R, Krammer F. Universal influenza virus vaccines and therapeutic antibodies. 2017;23:222-228.
- Heaton NS, Sachs D, Chen CJ, et al. Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins. Proc Natl Acad Sci U S A. 2013;110:20248-20253.
- Gerdil C. The annual production cycle for influenza vaccine. Vaccine. 2003;21:1776-1779.
- Paules CI, Marston HD, Eisinger RW, et al. The pathway to a universal influenza vaccine. Immunity. 2017;47:599-603.