Medium Article: Moving Towards a Universal Flu Vaccine?

            Influenza remains one of the most widespread and influential viruses in the world based on rates of infection, morbidity and mortality. The flu vaccine is humanity’s main prophylactic strategy to combat the seasonal spread of the virus. However, the vaccine effectiveness is variable and somewhat up to chance because researchers have to predict which strains and subtypes will be the most prevalent in the upcoming flu season and promote immunity solely against those specific virus types. Additionally, immunity decreases over the age of 65, as evidenced by the high rate of infection in older populations. Accordingly, researchers are looking for an alternative to the seasonal flu vaccine in what can serve as a “universal” influenza inoculation.

              In a recent paper by Rogers et al. (2019), a group of researchers performed a meta-analysis of the blood expression changes that occur with influenza infection compared to the vaccination. Furthermore, they identified genes that vary with age and sex all of which could be used to find gene targets for a potential universal vaccine. The researchers carried out the study by investigating 18 microarray datasets from influenza patients then used statistical analysis to filter out the genes that increase expression under flu infection, vaccination or both. Their screen yielded 978 unique “disease genes,” 334 if which overlap between vaccination and infection, notably the TANK gene which is a part of the NF-kappa B signal pathway. NF-kappa B is activated under a viral infection to up-regulate antiviral genes, and shows similar pattern between vaccination and disease. However, 664 genes are exclusively active under vaccination or infection. For example, CD40 and other antigen processing genes are only active under vaccination while other important immune mediators such as RIG-I-like receptors are actually down-regulated compared to infected subjects. Similarly, processes such as neutrophil degranulation and additional defense mechanisms only occur with a ‘real’ influenza infection. All of this is to say that the current vaccines do not induce a full-blown antiviral state and can even suppress important pathways in building a defense against the flu.

              The Rogers et al. study is an important – all be it, a small – first step in identifying gene candidates with a possible role during influenza infection and building immunity. With a more advanced understanding of how the body and immune system react to viral stimulation, the closer the scientific community can advance towards a smarter, universal vaccine. As far as next steps, the logical follow-up to the study is to explore the identified gene targets with either animal models or RNA-sequencing of human serum samples. The research also raises questions as the role and effect of all the disease genes, how they lead to pathology and side effects, and which are important for developing more comprehensive immunity.

              I found several strengths in the paper surrounding the quantity and types of patient data collected and utilized. In contrast to single, smaller studies, a meta-analysis gives researchers more statistical power, allowing them to uncover clearer patterns within the data and make more educated conclusions. Additionally, the authors had a large control group to compare with and accurately identify the unique “disease genes.” There were, however, some significant weaknesses in the methods. The authors were not able to acquire which vaccine type (trivalent, quadrivalent, year) each patient received, thereby missing the variation between different vaccinations. Each of the screens only included genes that were already previously known and investigated in an immunological study, so the study would not reveal a “new” immune gene. Finally, they did not know the influenza virus strain or subtype that the infected patients had and their pool of diseased individuals was significantly smaller than the other two experimental groups.

              So, how much closer does this “groundbreaking” study really bring us to a ‘universal’ flu vaccine and is this type of research even worth our time and resources? Personally, I am not incredibly optimistic that we will see a ‘universal’ vaccination in the next decade. And while the Rogers et al. paper can help narrow down gene targets and perhaps explain differences in immune responses between a vaccine and infection or amongst different ages, there is still a significant amount of work needed to delineate the function of each gene and design a drug that could target the correct immune mechanisms as an adjuvant. In another research endeavor, the authors took a different approach to developing a universal vaccine in which they expressed the influenza matrix 2 protein on bacterial surfaces to ‘train’ the immune system to recognize the antigen. The benefit of this alternative method is that all influenza A viruses express the M2, regardless of subtype. The most effective universal vaccine might involve a combination of immune stimulation and more “universal” antigen targeting.

              I think that many people would agree with me when I say that this research is well worth our hard-earned tax dollars (or privately financed funds). To explain why, let me share a personal anecdote of getting vaccinated during the 2009 Swine Flu (H1N1) pandemic. At the height of the outbreak, there was a major shortage of the newly approved H1N1 emergency vaccine. It had to be rationed, and high-risk populations – such as the elderly and immunocompromised – and health care providers were given first priority (plus high level “essential” administrators). My father – who works in the healthcare field and would never let his children be without the best, most recent inoculation – got special permission to use the ‘spare’ vaccines on my mother, my three brothers and me. So, we ‘snuck’ into the basement of the hospital so no one could see us getting the H1N1 vaccine. If we could have a more effective universal vaccine, pandemics like the Swine Flu outbreak could be even rarer and less impactful, and there may not be a need to make an ‘emergency’ inoculation against a novel viral strain. My hope is that research like the Rogers et al. study can galvanize future endeavors towards attenuating the global effect of the still omnipresent influenza virus.

~Avi Kaye

Article: Rogers, L., de los Campos, G., & Mias, G. Microarray Gene Expression Dataset Re-Analysis Reveals Variability in Influenza Infection and Vaccination. Frontiers in Immunology, 2019; 10 DOI: 10.3389/fimmu.2019.02616

Additional Reference: Anderton, K. “Universal influenza vaccine developed at Cornell is set for human clinical trials.” News Medical. https://www.news-medical.net/news/20191024/Universal-influenza-vaccine-developed-at-Cornell-is-set-for-human-clinical-trials.aspx