Flumist - What Went Wrong and Can it be Fixed?

[[{"type":"media","view_mode":"media_crop","fid":"55923","attributes":{"alt":"","class":"media-image media-image-right","height":"342","id":"media_crop_5769591985543","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"7020","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"©Mathagraphics/Shutterstock.com ","typeof":"foaf:Image","width":"251"}}]]This summer, the CDC made the interim recommendation to not use Flumist for the 2016-17 flu season due to low effectiveness against the H1N1pandemic strain two years in a row. On average, about one-third of pediatric influenza vaccinations were done with Flumist.  Most of my patients who had opted for Flumist last flu season year were willing to get the shot, but some remained unvaccinated due to their needle phobia.

As mentioned above, data suggest that Flumist underperformed as compared to the flu shot in the previous 2 flu seasons. A CDC sponsored study on 2,132 subjects aged 2-17 years showed an overall effectiveness of Flumist of 3% as compared to 63% for the inactivated vaccine for the 2015-2016 season. The maker of Flumist, AstraZeneca, initially pushed back against this recommendation and pointed to 4 other studies for the same season showing Flumist efficacy of 46% to 58%. One was a US AstraZeneca-sponsored study, but the other 3 were from sources with “no skin in the game.” The largest was a study in Finland by the Finnish government on 58,857 infants aged 24-35 months that showed a Flumist effectiveness rate of 58%. At the same time AstraZeneca recognized that all these studies showed a decreased efficacy for Flumist as compared to the shot. This trend was also noted in the 2014-2015 season. Drilling down on the data suggested that most of the problem has been with just one of the 4 strains in the vaccine, the H1N1 pandemic strain.

What is the most likely cause for the problem with Flumist?

A. Poor replication in the nose of the H1N1 strain.

B. Poor thermostability of the H1N1 strain to elevated temperature during shipping and storage.

C. Vaccine virus interference when a 4th flu strain was added to the trivalent formulation.

D. Reduced replication in the nose of children previously vaccinated with Flumist due to the induction of nasal IgA which the shot does not produce.

Answer and Discussion>>

Answers:

D is the least likely root cause. Both randomized/controlled and observational studies have looked at this question and found no decreased efficacy with previous Flumist use.

B was the leading candidate for the cause in the 2014-2015 season when the H1N1 strain was shown to degrade more easily with heat and a statistically significant correlation was noted between reduced Flumist effectiveness and higher outdoor temperatures during unloading at US distributors. But, a more heat-resistant strain was developed and used the next season (2015-2016) and the reduced efficacy did not change.

C is still a possibility and being looked at, but ...

A is the most likely answer: reduced replication in the nose. Live vaccine effectiveness depends upon adequate replication of the organism. Otherwise, an immune response is blunted. For example, MMR vaccination has to be delayed after blood transfusions and non-monoclonal IgG antibody administration since the antimeasles antibody in those products interferes with the replication of the attenuated measles strain in the vaccine. Studies have shown the H1N1 strain used recently in Flumist does not replicate as well in human nasal epithelium by a factor of 40-to 100-fold less as compared to control strains. These studies are on file with AstraZeneca and have not been published yet.

Can this be fixed? 

I would guess yes, but the timeline may make it difficult to know until the summer of 2017, way after the deadlines for providers to make their pre-order for flu vaccines. The WHO will announce the specific H1N1 pandemic strain in March 2017 for the 2017-2018 season. That strain will need to be attenuated and cold-adapted for Flumist by AstraZeneca. Clinical studies will then be done looking at antibody production and replication starting in early summer but are unlikely to be completed before the June meeting of the ACIP (which won’t meet again until October). The investigational plan will have input from the CDC and FDA as well as outside scientists, but I doubt Flumist will get the official ACIP (CDC) approval before the June meeting. I hope I am wrong.

The FDA is a totally separate agency and will likely approve Flumist for use next year as it did for this year. But without a change in the ACIP’s current stance that Flumist not be used, it is unlikely that much will be distributed.

Resources

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm508761.htm discusses the US and overseas flumist effectiveness studies

https://www.ncbi.nlm.nih.gov/pubmed/27613072 study showing relationship with weather and Flumist efficacy

https://www.cdc.gov/flu/about/season/flu-season-2015-2016.htm  CDC data on flu vaccine effectiveness

http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm508761.htm the FDA’s take on the Flumist problem