Progress toward a universal flu vaccine

[Ygggdrasil]

A paper in Nature Medicine reports data from a phase I clinical trial of a new flu vaccine strategy that targets the stalk of the influenza virus's HA protein, a region that has much less variation between different flu strains.

Existing flu vaccines contain weakened or inactivated influenza viruses with a mix of hemagglutinins (HAs), the proteins that stud their surfaces. These vaccines primarily aim to trigger antibody responses against HA’s top part, or head. Genetic changes in flu viruses rarely alter most of the head. But a small part of the head does reassort, or mutate, frequently, which allows new viral strains to dodge any immune memory and forces flu vaccinemakers to prepare new formulations each year, with updated HAs.

HA’s bottom portion, or stalk, is less apt to vary, and epidemiological studies have shown people who have been exposed to an influenza strain and developed antibodies to the stalk can ward off a wide variety of other strains. So, the new universal flu vaccine candidate, one of a handful in development, puts HA’s stalk front and center. The study shows for the first time that “you can develop a vaccine strategy that produces stalk-reactive antibodies in humans,” says virologist Florian Krammer of the Icahn School of Medicine at Mount Sinai, who co-leads a multi-institutional universal flu vaccines consortium funded by the U.S. National Institute of Allergy and Infectious Diseases and helped develop the candidate tested in the new trial. Other clinical trials testing stalk-based universal flu vaccine candidates have yet to report data.

https://www.sciencemag.org/news/202...vaccine-shows-promises-it-first-clinical-test

The study looked only at antibody production, so there is no data on whether the vaccine induces immunity yet, which will have to wait for larger phase II and phase III clinical trials. There's still a long way to go to developing a universal flu vaccine, but this study show that this one particular strategy might be viable.

Link to the paper:
A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial
https://www.nature.com/articles/s41591-020-1118-7

Abstract:

Seasonal influenza viruses constantly change through antigenic drift and the emergence of pandemic influenza viruses through antigenic shift is unpredictable. Conventional influenza virus vaccines induce strain-specific neutralizing antibodies against the variable immunodominant globular head domain of the viral hemagglutinin protein. This necessitates frequent re-formulation of vaccines and handicaps pandemic preparedness. In this completed, observer-blind, randomized, placebo-controlled phase I trial (NCT03300050), safety and immunogenicity of chimeric hemagglutinin-based vaccines were tested in healthy, 18–39-year-old US adults. The study aimed to test the safety and ability of the vaccines to elicit broadly cross-reactive antibodies against the hemagglutinin stalk domain. Participants were enrolled into five groups to receive vaccinations with live-attenuated followed by AS03-adjuvanted inactivated vaccine (n = 20), live-attenuated followed by inactivated vaccine (n = 15), twice AS03-adjuvanted inactivated vaccine (n = 16) or placebo (n = 5, intranasal followed by intramuscular; n = 10, twice intramuscular) 3 months apart. Vaccination was found to be safe and induced a broad, strong, durable and functional immune response targeting the conserved, immunosubdominant stalk of the hemagglutinin. The results suggest that chimeric hemagglutinins have the potential to be developed as universal vaccines that protect broadly against influenza viruses.

 

[Ygggdrasil]

Here's another article describing a new vaccine technology that could lead toward a "universal" flu vaccine (or at least one protective against a broader range of flu strains). All the research is still in the pre-clinical stages (testing in animals), so these have not yet been tested in humans to see if they are safe or effective:

Quadrivalent influenza nanoparticle vaccines induce broad protection
Boyoglu-Barnum et al. Nature 2021
https://www.nature.com/articles/s41586-021-03365-x

Abstract:

Influenza vaccines that confer broad and durable protection against diverse viral strains would have a major effect on global health, as they would lessen the need for annual vaccine reformulation and immunization. Here we show that computationally designed, two-component nanoparticle immunogens induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens contain 20 haemagglutinin glycoprotein trimers in an ordered array, and their assembly in vitro enables the precisely controlled co-display of multiple distinct haemagglutinin proteins in defined ratios. Nanoparticle immunogens that co-display the four haemagglutinins of licensed quadrivalent influenza vaccines elicited antibody responses in several animal models against vaccine-matched strains that were equivalent to or better than commercial quadrivalent influenza vaccines, and simultaneously induced broadly protective antibody responses to heterologous viruses by targeting the subdominant yet conserved haemagglutinin stem. The combination of potent receptor-blocking and cross-reactive stem-directed antibodies induced by the nanoparticle immunogens makes them attractive candidates for a supraseasonal influenza vaccine candidate with the potential to replace conventional seasonal vaccines.

 

[jim mcnamara]

So. We need to be able to find the epitope that mutates the least and target that. A great concept, one caveat:

With our low vaccination rates, will we not favor new wild versions of the epitope more quickly? In other words what we already do and do not do (with influenza vaccination) will let Natural Selection kick in rapidly. And generate new epitopes. The behavior is already our norm. See:

Chapter 8 War & Virulence - his take on dystopic populations and societies
Evolution of Infectious Disease,
1994 Oxford University Press
Paul W. Ewald, Associate Professor and Chair of Biology Amherst College

In other words -
Are we starting a high entropy effort? An endless string of booster vaccines, for example. The quasispecies concept applies to viruses, I believe.