Influenza, COVID-19 similarities may provide insight into CV protection of future vaccine
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Lessons previously learned with the seasonal influenza vaccine, especially its benefits in patients with CVD, may help in the development of a COVID-19 vaccine, according to a state-of-the-art review.
“Especially now on the cusp of the flu season in the global North, the biggest take-home [message] is to make sure that patients get their flu shot and make sure ... that everyone in primary care is making sure that ... patients get it,” Bahar Behrouzi, MSc, MD/PhD trainee in the cardiovascular division at Women’s College Hospital in Toronto, told Healio. “We’ve seen studies that 1 in 3 hospitalized patients with cardiovascular disease are not getting their flu shot, and that’s too many. There aren’t any current preventive measures against COVID-19, but we know that we have the flu vaccine and can use that to prevent potential cardiovascular complications from getting the flu in people who are at the highest risk.”
Jacob A. Udell, MD, MPH, cardiologist at Women’s College Hospital and the Peter Munk Cardiac Centre at Toronto General Hospital at the University of Toronto, and Cardiology Today Next Gen Innovator, told Healio that his team was in the process of planning this state-of-the-art review published in the Journal of the American College of Cardiology on influenza, its vaccine and CV outcomes before the COVID-19 pandemic, which then served as an opportunity to take what has been learned about influenza and potentially apply it to COVID-19.
“There’s lots of lessons we learned with regard to … flu vaccine protection, and what lessons can be learned and applied to the whole experience that we’re seeing on steroids with COVID-19,” Udell said in an interview. “More importantly, our colleagues in cardiology have a huge responsibility and opportunity to advocate for their patients. They potentially even could be the doctors who provide a flu shot … or at least know where to send their patients to get one. We wanted this review to empower and inform cardiologists, general internists and the general public about the lessons we’ve learned about the similarities, comparisons and contrasts between influenza and COVID-19, and what can we do to help protect our patients in the long run.”
Influenza and CV complications
Epidemics of seasonal influenza have been linked to increases in CV hospitalization and mortality, according to the review. Improved detection led to better recognition of CV complications of influenza and other respiratory virus infections, some of which include acute MI and HF events, especially in patients with or at risk for CVD.
Several mechanisms may support this link between the influenza infection and CV risk, including increased metabolic demand and exacerbation of underlying CVD. The virus may also precipitate acute CV events by triggering a potent acute inflammatory response, according to the review.
For COVID-19, several comorbidities may be linked to increased risk for needing critical care, including diabetes, advanced age, HF, hypertension and atherosclerotic CVD. Patients with these comorbidities eventually died of cardiopulmonary and acute CV events, including myocarditis, multiple organ failure, acute respiratory distress syndrome, shock, arrhythmias and HF. Research is still emerging as to the specific mechanisms on how SARS-CoV-2 can lead to acute myocardial injury. Some suspect that angiotensin-converting enzyme 2 (ACE2) receptor may play a role, according to the review.
Although influenza vaccines have been developed annually to adapt to circulating strains, their effectiveness may vary depending on how the vaccine antigen formulation matches with the strains themselves. H3N2, for example, is a strain with a lot of recently seen vaccine mismatch. The low effectiveness of the influenza vaccine against the H3N2 strain is more pronounced in older patients and others with high risk.
“The dirty little secret about flu shots that we don’t really give a lot of attention to is that the type of strain, the one that gives you the nasty pneumonias and potentially a lot of the cardiac complications, is the H3N2 strain,” Udell told Healio. “When we were planning the INVESTED trial, we thought in 2015-2016, the vaccine looked great against the H3N2 and other strains. Although flu shots are not the polio vaccine, we’re not expecting 100% protection, we can see in a year with a good match a 40% or 50% reduction in risk, we’ll take that. That level of risk reduction is considered great in cardiac trials. But with flu vaccines, over time, we have seen a waning immune response, particularly a waning effectiveness against the H3N2 flu strain since 2015. That was really concerning to us.”
Behrouzi also told Healio that this may be due to the manufacturing process of the vaccine. “A natural mutation has happened with the H3N2 flu virus, and that’s one of the ways in which we see more of a mismatch between the vaccine and this circulating strain of virus,” she said in an interview. “If you get a little bit of a mismatch, that reduces the effectiveness of the vaccine.”
WHO listed 142 candidate vaccines for COVID-19 in preclinical evaluation as of Aug. 28, and 33 were already in the clinical trial stage, according to the review. Even with a successful COVID-19 vaccine, the challenge with implementation lies in mass production. Other challenges include commonly circulating coronaviruses, the potential for the SARS-CoV-2 genome to mutate over time.
Although both influenza and COVID-19 increase the risks for acute MI and other CV events, at present, the influenza vaccine appears to reduce that CV risk, according to the review. Risk reduction may be caused by the vaccine interacting with inflammatory and immune systems to promote plaque stabilization, in addition to vaccine-induced antibodies interacting with the bradykinin 2 receptor to increase nitric oxide production.
“Vaccination will reduce the risk of influenza and may offer some incremental cardiorespiratory protection until a definitive COVID-19 vaccination is available,” Behrouzi and colleagues wrote.
Ongoing trials
Three large ongoing CV outcomes trials are currently assessing cardiorespiratory effects of the influenza vaccine, according to the review. The IVVE trial is comparing a standard-dose trivalent inactivated influenza vaccine with placebo with regard to a composite of adverse CV events in high-risk patients with NYHA functional class II to IV HF. In addition, the IAMI trial will assess a standard dose of a trivalent inactivated influenza vaccine in patients with STEMI or non-STEMI who are undergoing coronary angiography. Lastly, the INVESTED trial will compare a high-dose trivalent inactivated influenza vaccine with a standard-dose quadrivalent influenza vaccine in patients with a recent history of MI or HF hospitalization over four influenza seasons.
“There’s a lot of lessons that we’ve learned with regard to flu vaccine protection,” Udell told Healio. “It’s very different than doing an ACE inhibitor, ARNI or SGLT2 trial. It’s not a consistent treatment effect year to year. It’s a humbling experience. Whether or not these lessons can be applied to COVID-19 will be very important to see how it all plays out in the next year or so.”
Udell added that this review serves as a reminder to the community about these opportunities to learn more. He said: “That’s part of why we wrote the paper. We wanted people to know about these trials, that they’re reporting soon, and we have this opportunity now to further leverage our trial networks to potentially study experimental vaccine protection from COVID-19.”
For the latest news on COVID-19 including case counts, information about the global public health response and emerging research, please visit the COVID-19 Resource Center on Healio.
For more information:
Bahar Behrouzi, MSc, can be reached at bahar.behrouzihoma@mail.utoronto.ca; Twitter: @baharbehrouzi.
Jacob A. Udell, MD, MPH, can be reached at jay.udell@utoronto.ca; Twitter: @jayudell.
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