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Building better flu vaccines is daunting



Vaccine-related factors

It’s likely that the availability of the flu vaccine for the upcoming 2019-2020 season is going to be delayed because of late selection of the strains for inclusion. The World Health Organization ordinarily selects strains for vaccines for the Northern Hemisphere in February, giving vaccine manufacturers 6-8 months to produce their vaccines and ship them in time for administration from September through November. This year, however, the WHO delayed selection of the H3N2 component until March because of the high level of antigenic and genetic diversity of circulating strains.

“This hasn’t happened since 2003 – it’s a very rare occurrence – but it does increase the potential that there’s going to be a delay in the availability of the vaccine in the fall,” he explained.

Eventually, the WHO selected a new clade 3C.3a virus called A/Kansas/14/2017 for the 2019-2020 vaccine. It should cover the circulating strains of H3N2 “reasonably well,” according to the physician.

Another issue: H3N2 has become adapted to the mammalian environment, so growing the virus in eggs introduces strong selection pressure for mutations leading to reduced vaccine effectiveness. Yet only two flu vaccines licensed in the United States are manufactured without eggs: Flucelvax, marketed by Seqirus for patients aged 4 years and up, and Sanofi’s Flublok, which is licensed for individuals who are 18 years of age or older. Studies are underway looking at the relative effectiveness of egg-based versus cell culture-manufactured flu vaccines in real-world settings.

Host factors

Hemagglutinin imprinting, sometimes referred to as “original antigenic sin,” is a decades-old concept whereby early childhood exposure to influenza viruses shapes future vaccine response.

“It suggests there could be some birth cohort effects in vaccine responsiveness, depending on what was circulating in the first 2-3 years after birth. It would complicate vaccine strategy quite a bit if you had to have different strategies for different birth cohorts,” Dr. Belongia observed.

Another host factor issue is the controversial topic of negative interference stemming from repeated vaccinations. It’s unclear how important this is in the real world, because studies have been inconsistent. Reassuringly, Dr. Belongia and coworkers found no association between prior-season influenza vaccination and diminished vaccine effectiveness in 3,369 U.S. children aged 2-17 years studied during the 2013-14 through 2015-16 flu seasons (JAMA Netw Open. 2018 Oct 5;1[6]:e183742. doi: 10.1001/jamanetworkopen.2018.3742).

“We found no suggestion at all of a problem with being vaccinated two seasons in a row,” according to Dr. Belongia.

How to build a better influenza vaccine for children

“I would say that even before we get to a universal vaccine, the next generation of flu vaccines that are more effective are not going to be manufactured using eggs, although we’re not real close to that. But I think that’s eventually where we’re going,” he said.

“I think it’s going to take a systems biology approach in order to really understand the adaptive immune response to infection and vaccination in early life. That means a much more detailed understanding of what is underlying the imprinting mechanisms and what is the adaptive response to repeated vaccination and infection. I think this is going to take prospective infant cohort studies; the National Institutes of Health is funding some that will begin within the next year,” Dr. Belongia added.

Many investigational approaches to improving influenza virus subtype-level protection are being explored. These include novel adjuvants, nanoparticle vaccines, computationally optimized broadly reactive antigens, and standardization of neuraminidase content.

And as for the much-desired universal flu vaccine?

“I will say that if a universal vaccine is going to work it’s probably going to work first in children. They have a much shorter immune history and their antibody landscape is a lot smaller, so you have a much better opportunity, I think, to generate a broad response to a universal vaccine compared to adults, who have much more complex immune landscapes,” he said.

Dr. Belongia reported having no financial conflicts regarding his presentation.

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