Flu (Influenza)

Half-Dose Influenza Vaccine Study

In June 2000, just after news surfaced of a possible delay or reduction in the availability of flu vaccine for the 2000-01 winter season, NIAID staff began discussing the possibility of conducting a trial to determine immune responses to half-dose flu vaccine in healthy young adults. The idea came from small studies published in the late 1970s suggesting that lower-than-full-dose influenza vaccines might provide adequate immunity against influenza virus infection.

NIAID and its clinical investigators worked quickly with the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) to develop a study protocol. The protocol was written and an Investigational New Drug Application filed with the FDA within three weeks. The application underwent an expedited review at the FDA.

The trial, conducted primarily through NIAID's Vaccine and Treatment Evaluation Units (VTEU) network, began recruiting patients on August 9, 2000. Within 13 days, 1,009 volunteers had been enrolled.

The VTEU, established by NIAID in 1962, is a network of university-based clinical sites set up to conduct safety and efficacy trials of promising vaccine strategies. The multicenter half-dose flu vaccine trial is an excellent example of the time-tested capability of the VTEU to quickly recruit and retain diverse populations into vaccine trials whose results may have profound effects on public health.

The half-dose flu study included the following five VTEU sites and NIAID's Respiratory Pathogens Research Unit at Baylor:

• New York—University of Rochester, Dr. John Treanor (Study Chair)
• California—UCLA Center for Vaccine Research, Dr. Ken Zangwill
• Maryland—University of Maryland, Dr. Robert Edelman
• Missouri—Saint Louis University, Dr. Robert Belshe
• Ohio—Cincinnati Children's Hospital, Dr. Gil Schiff
• Texas—Baylor College of Medicine, Dr. Wendy Keitel

To be eligible for the half-dose flu trial, volunteers had to be in good health and between the ages of 18 and 49 years old. Persons who were pregnant, allergic to eggs, or suffering from a chronic medical condition that could weaken the immune system were not eligible.

Investigators assigned each volunteer at random to receive an intramuscular injection of either a full dose (0.5 milliliter, ml) or half dose (0.25 ml) of an approved, inactivated influenza vaccine. A total of 505 individuals received full-dose vaccine and 504 received half-dose vaccine. Volunteers had blood samples drawn before vaccination and approximately three weeks later.

The purpose of the study was to determine if half the currently recommended dose of influenza vaccine might provide adequate levels of immunity in healthy young adults. The investigators evaluated immunity by measuring levels of antibodies to the influenza virus. Because this was not an efficacy study, volunteers were not challenged with influenza virus after receiving the vaccine, and they were not studied to see if they came down with influenza. The blood samples were sent to two laboratories, one at the CDC and one at the FDA, for independent testing for anti-influenza antibodies.

The product used in the study was an inactivated influenza vaccine manufactured by Evans Vaccines Ltd. (United Kingdom), formerly known as MEDEVA. It contained two influenza A strains (H3N2 and H1N1) and one influenza B strain. The results obtained from this study may not apply to influenza vaccines produced by other manufacturers.

Preliminary results of the study were presented at the Advisory Committee on Immunization Practices Meeting in Atlanta on October 18, 2000. Final results of the study, explained below, were published in the January 15, 2002 issue of Vaccine. (J. Treanor, et al. Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults. Vaccine 20(7-8): 1099-105. 2002.)

As expected, the immune responses to the full dose were higher, on average, than immune responses to the half dose vaccine. Should a public health emergency arise, however, the data support that administration of a half-dose influenza vaccine to healthy adults might be an acceptable strategy if the vaccine supply is substantially limited.

The study was designed such that the "acceptability" of a half dose would require that—

1. The post-vaccination ratio of antibody levels of the whole dose to the half dose should be no more than 1.5.
2. The difference in the number of individuals in the two groups whose antibody levels reached a standard of 1:32 or greater would be no more than 20 percent.
3. The difference in the standard four-fold increase in post-vaccination antibody levels over pre-vaccination vaccine levels between the two groups would be no more than 20 percent.

All three antigens in the vaccine (H1N1, H3N2, B) met, and actually exceeded, the acceptability criteria.

These data are of interest to determine if the vaccine supply might be extended during an emergency situation in the future, such as a substantial vaccine shortage possibly caused by manufacturing problems. However, it is likely that additional studies would be needed to confirm these results and answer other questions before a decision to use a half-dose influenza vaccine in healthy adults might be considered.

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