Is it appropriate to recommend a reformulated vaccine without additional effectiveness data?

Issue: November 2018

In February, the CDC’s Advisory Committee on Immunization Practices recommended a reformulated version of the FDA-approved live-attenuated influenza vaccine, or LAIV — marketed as FluMist — after its manufacturer had presented evidence showing the modified vaccine would perform better against influenza A(H1N1) than it had in previous influenza seasons. Infectious Diseases in Children asked Matthew Zahn, MD, chair of the Infectious Diseases Society of America’s Public Health Committee, the ACIP liaison for the National Association of County and City Health Officials, and medical director of the epidemiology program for Orange County, California, Health Care Agency, if it is appropriate for the ACIP to recommend an FDA-approved quadrivalent vaccine that was reformulated due to a lack of effectiveness against one vaccine strain without first seeing additional effectiveness data against that particular strain.

Earlier this year, the ACIP again recommended that quadrivalent LAIV be considered as an influenza vaccination option for those for whom it is appropriate, with no preference for any influenza vaccine product. The poor effectiveness of LAIV against influenza A(H1N1)pdm09 during the 2013-2014 and 2015-2016 seasons had previously led ACIP to not recommend LAIV for use during the 2016-2017 and 2017-2018 seasons.

The manufacturer of FluMist, the sole LAIV used in the United States, found that the strains used in the 2013-2014 and 2015-2016 seasons (A/California/7/2009 for the 2013-2014 season and A/Bolivia/559/2013 for 2015-2016 season), replicated less well compared with older LAIV strains. Following the 2015-2016 season, the manufacturer reconfigured LAIV by switching to a new H1N1 post-pandemic strain (A/Slovenia/2903/2015). In a subsequent study of pediatric patients, the manufacturer found that the A/Slovenia/2903/2015 strain was shed by a higher proportion of children during days 4 through 7 following the first of two doses of vaccine. The A/Slovenia/2903/2015 strain also induced significantly higher antibody responses than A/Bolivia/559/2013, with seroconversion rates comparable to pre-pandemic influenza A(H1N1) LAIV strains used during seasons in which the vaccine was observed to be effective against A(H1N1) infection.

This study provides evidence that a plausible root cause of LAIV’s reduced effectiveness has been addressed.

It is not the same as demonstrating vaccine effectiveness (VE) by measuring the degree of protection provided to patients in routine clinical settings. In the past, influenza serologic and shedding studies have not always correlated with VE.

However, obtaining effectiveness data is a circular problem: The vaccine needs to be used widely in order for VE data to be gathered in this country, but such data will not be available until the vaccine is again widely recommended in the U.S. In future years, additional VE data will likely be available from other countries, where LAIV is used, including Canada and multiple European countries. However, data from other countries have indicated higher point estimates of effectiveness compared with U.S. data in the past, and it is not clear how they can be interpreted to guide U.S. vaccination policy. The reformulated vaccine has been used in other countries during the 2017-2018 season, but it was an H3N2-predominant influenza season and thus provided little information regarding H1N1 effectiveness. The ACIP made its recommendation based upon currently available data, recognizing that additional definitive data are not likely to be available soon.

LAIV has played an important role in protecting against influenza for many years. Prior to the 2009 H1N1 influenza pandemic, multiple randomized trials found superior relative efficacy of the trivalent LAIV compared with trivalent inactivated influenza vaccine among children, which led to a preferential recommendation among children aged 2 to 17 years during the 2013-2014 season. Many people have grown accustomed to getting vaccinated “without the shot.” Although national immunization rates did not drop overall when LAIV was taken off the market, local data are likely to vary. There may be detrimental effects from the loss of opportunities to immunize, such as school-based immunization programs, which are being curtailed.

We know that influenza VE varies from year to year for all vaccine types. Inactivated influenza VE for the 2017-2018 season was estimated to be 24%, despite what was felt to be a good vaccine match with prevalent H3N2 strains. The vaccine’s poor effectiveness has been postulated to be due to the acquisition of adaptive changes in the hemagglutinin protein, which alter antigenicity in H3N2 vaccine viruses grown in eggs. This issue has been addressed by using a new influenza H3N2 strain in the vaccine this year, but as always, close surveillance will be vital to ensure VE going forward. The poor effectiveness of LAIV against H1N1 for multiple seasons using multiple H1N1 vaccine strains is of particular concern. However, with the evidence provided by the manufacturer that the underlying issue has been identified and addressed, it seems appropriate to reintroduce LAIV, with close monitoring for LAIV effectiveness in the future, particularly during H1N1-predominant seasons.

Although influenza VE varies from year to year, we also know that each year influenza vaccination saves thousands of lives. The long-term goal is to develop a vaccine that provides consistent protection that does not require year-to-year modification in response to prevalent strains. In the meantime, vaccine manufacturers in concert with public health must work to identify and address effectiveness issues as they arise.

Finally, it is worth noting that, historically, influenza VE data have not been used to establish the superiority of one vaccine vs. another. As VE surveillance becomes more robust, we will need to continue to learn how to best use these data to guide policy.

Editor’s note: Public Health England published provisional end-of-season adjusted vaccine effectiveness estimates from the 2017-2018 influenza season. The data can be found here.

Disclosure: Zahn reports no relevant financial disclosures.