CVD Flu Vaccine Trial Infrastructure May Inform COVID-19 Trials

Debra L. Beck

October 08, 2020

The infrastructure, know-how, and capacity developed for three ongoing cardiovascular outcomes trials (CVOT) of vaccines against influenza may provide a roadmap for testing novel interventions against COVID-19 in cardiovascular disease patients.

The first of these trials, titled INVESTED, is set to present findings in a late-breaking science session at the American Heart Association 2020 Scientific Sessions next month.

"I think we'll have a good COVID-19 vaccine, but it may take a village to compare the candidate vaccines and really understand if they reduce cardiovascular risk in our patients," said Jacob A. Udell, MD, MPH, from Women's College Hospital and Peter Munk Cardiac Centre at the University of Toronto, Toronto, Canada.

"Having built capacity and taught cardiologists how to give flu shots to heart patients over the last 5 years, I think we are well positioned to do the same with a COVID vaccine and help out with that discovery science," he added.

Udell is the senior author of a JACC State-of-The-Art Review just published online October 5. The review traces the current state of influenza vaccine research in cardiovascular patients and compares what is known from influenza to what has been learned to date about COVID-19.

Although there is solid evidence from observational studies that influenza vaccination reduces the risk of adverse events in patients with CVD, there have been few controlled trials supporting this.

The NIH-funded INVESTED trial enrolled 5266 patients at 190 sites in the US and Canada and compared the high-dose trivalent inactivated influenza vaccine (IIV3-HD) against the standard-dose quadrivalent inactivated influenza vaccine (IIV4). The primary endpoint is a composite of all-cause mortality or cardiopulmonary hospitalization.

Besides INVESTED there are 2 other large ongoing CVOTs looking at the cardioprotective effects of influenza vaccination.

One trial, called IAMI, was supposed to have results ready by last month. Because of COVID-19, this trial has reduced enrollment to 2573 (from a planned 4400) and will not release primary results until next August. It's testing a composite endpoint of time to all-cause death or a new myocardial infarction (MI) or stent thrombosis at 1 year.

The third trial, RCT-IVVE, has enrolled 4871 patients with NYHA class II-IV heart failure at 10 sites in Asia, the Middle East, and Africa (10 countries), and will present initial results in May. That trial is comparing the standard dose vaccine (IIV3) with placebo for a composite endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure at 6 months.

Flu Vaccine May Get a Lift From COVID-19 Vaccine?

The review, which is coauthored by the leaders of all three CVOT trials along with first author Bahar Behrouzi, MSc, also from University of Toronto, offers a possible path to greater influenza vaccine effectiveness, which has been waning for several years now.

It’s a "dirty little secret" in the infectious disease world that influenza vaccine effectiveness has been consistently dropping over the past few years, said Udell in an interview with | Medscape Cardiology.

"If you look at the last 5 years of comparative effectiveness data from the CDC that we include in our paper, it's quite clear that effectiveness is going down, in particular in the elderly, who most need the cardioprotection we think the vaccine affords, and for the most virulent strains, like H1N1 and H3N2 that cause the most severe illness," he said.

The key factor in determining vaccine effectiveness, according to the review, is related to how well the vaccine antigen formulation matches the viral flu strains circulating each year. In the past 4 years, the prediction has been low in the United States.

But vaccine mismatch isn't just about how well the virologists predict the prevalent strains. It can also occur during manufacturing, Udell said.

"The mass manufacturing of flu shots in 2020 is still happening the same way we did it in 1918, which is by using chicken eggs. The problem is that it turns out viruses are pretty smart and they can mutate during replication in the eggs, leading to something called 'egg-adaptation.' "

It appears the H3N2 influenza strain is particularly prone to glycosylation mutations in the antigenic sites of hemagglutinin, something that was noted as early as 2014. These new mutations are not present in current egg-adapted versions of the H3N2 strains, resulting in poor effectiveness.

Based on the CDC data from the 2018-2019 season, the effectiveness of the flu vaccine against H1N1 and H3N2 in individuals 65 years of age and older was about 18% and 12%, respectively. This is compared to effectiveness rates of about 65% and 42%, respectively, in that age group for those two strains in the 2015-2016 season.

In younger people, effectiveness in 2018-2019 for H1N1 was above 40%, dropping to about 10% for H3N2.

"What's driving overall vaccine effectiveness to appear higher is the H1N1 strain, which has not adapted and is still getting pretty good coverage from the vaccine, but it's the low effectiveness against H3N2, particularly in the elderly population, that is really a problem," said Udell.

So, while egg-based vaccine manufacturing is cost-effective and readily available, new techniques are needed that can overcome this issue of egg-adaptation and antigenic drift.

Egg-based vaccine manufacturing is used to make both inactivated vaccines, like the flu shot, and live attenuated (weakened) vaccines, like the nasal spray flu vaccine.

"Fortunately, there are innovations to vaccine manufacturing that are happening right now that may help us improve on effectiveness," said Udell.

It turns out the high-speed development of vaccines against COVID-19, and the concurrent development of mass manufacturing capability to produce said vaccines, will likely offer opportunities to greatly improve influenza vaccine effectiveness down the line. 

"Recombinant vaccines use reverse transcriptase of RNA that forgoes any kind of processing happening in the egg. You get rid of all that because you give the RNA of the actual virus and it produces the right copy of the antibody, an exact match," said Udell.

"The bad news is that we don't have the manufacturing capability to produce these kinds of vaccine en masse. The good news is that because of COVID-19 these capabilities are being greatly expanded worldwide," he added.

Udell reports he has received research support from a handful of public entities and has served as a consultant for Amgen, Boehringer Ingelheim, Janssen, Merck, Novartis, and Sanofi. 

J Am Coll Cardiol. Published online October 5, 2020. Abstract

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