Why doesn't the CDC or WHO offer more seasonal flu candidate vaccine viruses (CVVs)? originally appeared on Quora, the place to gain and share knowledge, empowering people to learn from others and better understand the world. You can follow Quora on Twitter, Facebook, and Google Plus.

Why doesn't the CDC or WHO offer more seasonal flu candidate vaccine viruses (CVVs)? Given that it takes a long time to grow the vaccine to make a flu shot, why not make several versions and pick the most effective at the time of flu shot injections?

This answer briefly covers:

* The global seasonal flu vaccine production process: how it starts, the key players, etc.

* How egg-based flu vaccine production is its major bottleneck.

The clock for the Northern Hemisphere annual seasonal flu vaccine starts in February with the WHO, which coordinates the Global Influenza Surveillance and Response System (GISRS), a group of 143 WHO-designated National Influenza Centers (NICs) in 113 WHO Member States plus 6 WHO Influenza Collaborating Centers and several Regulatory and Reference labs.

* These NICs isolate the viruses presently circulating in their countries/regions and submit them to CCs which conduct detailed antigenic analysis to determine the influenza A and B subtypes.

* The WHO then makes a worldwide recommendation of the influenza A and B strains to be used for the upcoming season's vaccine, which needs to be adapted to the local epidemiological situation in each country/region.

* For example, the FDA makes the local decision in the US by selecting the strains to include for that year in the US.

See sequentially below text from 1, emphasis mine, and table from 2.

'These WHO recommendations provide a guide to national public health and regulatory authorities and vaccine manufacturers for the development and production of influenza vaccines for the next influenza season. In contrast to many other vaccines, the viruses in influenza vaccines have to be evaluated and updated regularly because circulating influenza viruses continuously evolve. Recommendations are made in February/March for the following influenza season in the northern hemisphere and in September for the following influenza season in the southern hemisphere because approximately 6-8 months are needed to produce and approve vaccines. WHO has formulated guidance for countries in tropical and sub-tropical regions to assist them in choosing which vaccine composition (February/March or September) is most appropriate (Seasonal influenza vaccine in tropics and subtropics).' Using eggs to grow seasonal flu vaccine is the major bottleneck in its production (see chart from 3).

Using eggs to grow seasonal flu vaccine is the major bottleneck in its production (see chart from 3).

Egg-based flu vaccines have all sorts of drawbacks:

* They take at least 6 months, a length of time that ends up creating other problems.

* Logistically, vaccine design can't be tweaked on a dime midway and yet sufficient amounts need to be made in time for flu season once the annual process starts.

* Egg supply can be threatened or inadequate during avian flu epidemics.

* Currently the decision for which flu strains should be included is made ~9 months before the start of the next flu season to give enough time to produce and distribute the vaccine. This decision is based on an early snapshot which gives a longer window of opportunity for new antigenic variants to emerge among the strains circulating in the human population, the so-called mismatch issue caused by flu virus' prodigious ability to engage in Antigenic drift.

* The longer it takes to grow the flu strains inside chicken eggs, the greater the opportunity for flu virus variants to emerge. Often this process-associated limitation is the reason for reduced flu vaccine efficacy.

* Egg-adapted flu strains can often be antigenically different and thus may end up driving immune responses to such irrelevant antigens rather than to those that are expressed by the circulating flu strains that are infecting humans during a given flu season (4).

* While such mutation propensity was observed all the way back in 1980 (5), frequent occurrences of low flu vaccine effectiveness in recent years has now made it a front and center issue.

* Egg-adaption induced mutations in flu strains seem to be especially a problem with H3N2 flu strains (6),which seem prevalent in the 2017-2018 flu season.

These types of process-associated artifacts are frequently the reason for low flu vaccine efficacy. So what to do about it? Other approaches to produce seasonal flu vaccine include cell-based, recombinant protein-based or plant based (see chart from 7).

The problem is that such approaches have been discussed and explored for years but none has yet broken through into the mainstream. Reasons for delay include the protracted length and expense for each approach to pass muster, which requires the expensive proposition of undertaking a series of clinical trials that pass the benchmarks for safety and efficacy. While these approaches are being put to the test in this fashion, none is yet close to the finish line.

Another is the holy grail of universal flu vaccines (8, 9). The hold up there is:

* Incomplete knowledge of what an effective immune response to flu entails.

* Which specific immune response elements are both necessary and sufficient.

* Different studies spotlight different features while what constitutes a flu Correlates of immunity/correlates of protection is still a matter of debate.

Thus, notwithstanding its many drawbacks including variable efficacy, given its proven track record of safety, and tried and tested production process, the 70 year old egg-based seasonal flu vaccine unfortunately currently remains a mainstay.

Bibliography

1. http://www.who.int/influenza/vac...

2. Brooks, W. Abdullah, and Mark C. Steinhoff. "Epidemiology of influenza in tropical and subtropical low-income regions." Influenza vaccines for the future. Springer, Basel, 2011. 55-75. https://the-eye.eu/public/Books/...

3. http://www.multivu.com/players/E...

4. Raymond, Donald D., et al. "Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain." Nature medicine 22.12 (2016): 1465. https://crystal.harvard.edu/PDFs...

5. Brand, Colin, and Peter Palese. "Sequential passage of influenza virus in embryonated eggs or tissue culture: emergence of mutants." Virology 107.2 (1980): 424-433.

6. Skowronski, Danuta M., et al. "Low 2012–13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses." PloS one 9.3 (2014): e92153.

7. Effectiveness of the seasonal flu vaccine and new production methods

8. Paules, Catharine I., et al. "The Pathway to a Universal Influenza Vaccine." Immunity 47.4 (2017): 599-603.

9. Paules, Catharine I., et al. "Chasing Seasonal Influenza—The Need for a Universal Influenza Vaccine." New England Journal of Medicine 378.1 (2018): 7-9. http://www.nejm.org/doi/pdf/10.1...

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