The rapid global spread of a novel type of H1N1 influenza A, commonly referred to as "swine flu," has led the World Health Organization to declare the first influenza pandemic in 41 years. In the northern hemisphere, the incidence of H1N1 infection is likely to increase substantially in the upcoming flu season, with major public health ramifications. An article in the September 10, 2009 advance online issue of the New England Journal of Medicine reviewed preliminary results of a study suggesting that a single 15 microgram (mcg) dose of an investigational H1N1 vaccine was well tolerated and induced a strong immune response in healthy adults.

By Ronald Baker, PhD

Shortly after the identification of the 2009 H1N1 strain, flu vaccine manufacturers, in conjunction with public health and regulatory agencies, started developing vaccine candidates with a sense of urgency. In the current study, Australian researchers conducted a clinical trial of healthy adults to examine the immunogenicity (ability to stimulate an immune response), safety, and tolerability of 2 different doses of an investigational 2009 H1N1 influenza vaccine.

The investigators examined a 2-dose regimen of either 15 mcg or 30 mcg of hemagglutinin antigen, because there was uncertainty as to whether a higher antigen content or a 2-dose series might be required to produce a satisfactory response.

The study enrolled equal numbers of participants above and below 50 years of age in order to explore potential age-related differences in immune response. The preliminary report includes results available to date from the ongoing study after the first of 2 scheduled vaccinations.

Results

	By day 21 after vaccination, antibody titers of 1:40 or more were observed in 116 of 120 participants (96.7%) who received the 15 mcg dose and in 112 of 120 participants (93.3%) who received the 30 mcg dose.
	No deaths, serious adverse events, or adverse events of special interest were reported.
	46.3% of participants reported local discomfort (e.g., injection-site tenderness or pain) and 45.0% reported systemic symptoms (e.g., headache).
	Nearly all adverse events were mild to moderate in intensity.

Based on these results, the study authors concluded, "A single 15-microgram dose of 2009 H1N1 vaccine was immunogenic in adults, with mild-to-moderate vaccine-associated reactions."

Discussion

The authors noted several points in the "Discussion" section of their article; following are a few excerpts:

	The robust immune response to the H1N1 vaccine after a single dose was unanticipated, according to the authors. Much of the current global pandemic planning is based on previous experience indicating that 2 doses of vaccine are required to elicit a protective immune response in populations that are immunologically naive (previously unexposed) to a new influenza strain.
	The proportion of study participants with antibody titers of 1:40 or more on a hemagglutination-inhibition assay at baseline was higher than expected. Among participants age 50 or older, this finding might be attributed to the presence of pre-existing antibodies from exposure to H1N1 viruses circulating before 1957. It was surprising, however, to see similar baseline antibody titers in the younger age group.
	Several important questions remain unanswered in this trial. First, since the researchers studied healthy adults, trials still must be conducted in other populations that may have different responses to the vaccine, such as the elderly, children, and people with impaired immunity (including HIV positive people).
	Second, given the robust immune response to a 15 mcg dose, lower antigen doses should be explored.
	Third, given that this study was conducted in a single locality in Australia during winter in the southern hemisphere, the findings need to be confirmed by studies in other locations where the epidemiology of the pandemic may be different.
	Finally, estimates of the true effect of the vaccine when used in mass immunization programs will need to come from vaccine effectiveness studies.

The clinical trial reported here is being conducted by the Clinical Research and Development Department of CSL Limited of Parkville, Victoria, Australia.

9/15/09

Reference
ME Greenberg, MH Lai, GF Hartel, and others. Response after One Dose of a Monovalent Influenza A (H1N1) 2009 Vaccine -- Preliminary Report. New England Journal of Medicine. September 10, 2009 (Epub ahead of print). (Abstract).