Why Live Attenuated Influenza Vaccine Should Be Kept Cool

The World Health Organization and national public health bodies assess influenza vaccine effectiveness continuously so they can make reasonable recommendations.

Countries around the world support annual observational studies of vaccine effectiveness using a prospective, test-negative case control (TNCC) design. The rationale for TNCC studies is that they are operationally feasible and more ethical than randomized, placebo-controlled, prospective trials. However, TNCC studies are vulnerable to bias, and small sample sizes can inflate or depress estimates.

Manufacturer-initiated TNCC studies were used to evaluate the effectiveness of live attenuated influenza vaccine (LAIV) among children 2 to 17 years during 4 consecutive influenza seasons to fulfill an FDA regulatory requirement. The CDC also conducted TNCC studies concurrently.

These studies reported a lack of significant vaccine effectiveness when LAIV was administered to children during a season dominated by A/H1N1pdm09 strains. This was unexpected, particularly because previous randomized, controlled trials in children demonstrated high vaccine effectiveness, and a manufacturers’ TNCC study reported high and statistically significant effectiveness against circulating B strains.

The search for explanations began as soon as these results were announced. One potential explanation may be improper storage, as an article published ahead-of-print in the journal Vaccine suggests.

LAIV and all live vaccines are susceptible to heat degradation. Their labeling indicates that they should be stored and transported at refrigerated temperatures.

The A/California/2009/07 viral strain is more sensitive to heat than other strains due to reduced hemagglutinin stability. Temperature excursions during vaccine shipping and handling might explain low VE against A/H1N1pdm09 strains.

A team of researchers conducted a comprehensive review of the available data from TNCC and randomized studies describing LAIV vaccine effectiveness in children from 2009 to 2010 through 2013-2014 to try to determine why LAIV’s effectiveness against H1N1pmd09 strains in the United States in 2013-2014 was so low.

Exposure of some LAIV lots to heat during US distribution may explain its poor performance in 2013—2014. Vaccine shipping date and ambient temperatures were significantly associated with reduced vaccine effectiveness. LAIV lots shipped between August 1 and September 15 or unloaded at distributors at a time when outdoor temperatures exceed 84^oF (29^oC) were more likely to have reduced vaccine effectiveness.

LAIV’s effectiveness was high when lots were shipped before August or after mid-September 2013, and very close to expected effectiveness when it was unloaded at temperatures below 84^oF (29^oC).