3 H1N1 vaccine studies confirm safety, weigh dosing

Large trials in the United States, Hungary and China recently confirmed the safety and efficacy of H1N1 vaccines, yielding new insights on how to best use vaccines in a pandemic setting, CIDRAP News reported Jan. 4.

The three studies appeared in the Jan. 2 issue of The Lancet. All involve some of the pandemic H1N1 vaccines that are already approved and are in use. The new reports flesh out preliminary findings that regulators used to make their decisions in the summer and fall of 2009 but differed on the effectiveness of immune-boosting adjuvants.

Each of the three studies used a different design that could help public health officials fine-tune their vaccination strategies.

Investigators from all three countries reported no deaths from the vaccine, with mostly mild or moderate adverse reactions, confirming the pandemic vaccine safety assessments of national authorities and World Health Organization experts.

The U.S. study consisted of two phase 2 trials of Sanofi Pasteur's licensed pandemic H1N1 vaccine: one in adults (497 ages 18 to 64 and 352 older than 65) and one in children (229 ages 6 to 35 months and 245 ages 3 to 9 years).

The researchers concluded that even the lowest antigen dose they used in adults, which contained half of the amount used in the nation's approved vaccines, exceeded the U.S. Food and Drug Administration's immunogenicity requirements for the age groups. They wrote that their findings confirm that just one dose is needed in adults and that children younger than 9 years probably need two doses to meet the FDA's efficacy criteria.

Safety findings suggest the profile of the pandemic vaccine is similar to that of seasonal flu vaccines, the group wrote. They added that they are still studying the efficacy and safety of a two-dose vaccine regimen in children.

In the Hungarian study, researchers compared the safety and efficacy of the country's licensed pandemic vaccine in adults when administered alone and alongside the seasonal flu vaccine.

The pandemic vaccine they evaluated is made by Omnivest and is a whole-virus inactivated vaccine that contains 6 mcg of antigen per dose along with an aluminum phosphate adjuvant. Omnivest, based in Hungary, also makes the country's seasonal flu vaccine and a pre-pandemic H5N1 vaccine. Hungary began its pandemic vaccine campaign at the end of September.

The study group included 203 adults ages 18 to 60 and 152 adults older than 60.

People who received just the pandemic vaccine showed a strong immune response against the pandemic H1N1 virus, and those who received both vaccines showed a strong response against the pandemic strain, plus the seasonal strains.

The researchers concluded that their findings suggest one dose of the pandemic vaccine is enough for both adults and seniors. "Inclusion of elderly participants is important, since influenza-based morbidity and mortality increase with age, especially for individuals with high-risk diseases," they wrote.

They also added that the finding that pandemic H1N1 and seasonal flu vaccine co-administration is safe and effective is useful for pandemic planners who must manage vaccine logistics.

Chinese researchers tested eight formulations of pandemic H1N1 vaccine made by 10 of the country's manufacturers, plus a placebo. The multicenter study involved 12,691 people age 3 and older who received two doses 21 days apart.

The eight formulations included adjuvanted and nonadjuvanted versions of split-virus vaccines that contained 7.5, 15, and 30 mcg of antigen per dose. Researchers also evaluated whole-virus adjuvanted pandemic H1N1 vaccines that contained 5 or 10 mcg per dose.

The researchers found that the boosting effect of the second dose was more pronounced in children, but had limited effect in other groups.

Though the group found that all versions of the vaccine were safe and effective, they noted that the nonadjuvanted 7.5-mcg formulation induced almost the same immune response as vaccine formulations containing more antigens, which could be useful during a pandemic when vaccine is in short supply. However, they added that children ages 3 to 12 might need a second dose to achieve acceptable protection.

Also, they said the findings suggest the adjuvanted formulations were less effective, which was perplexing and might relate to aluminum absorption causing a delay in antigen release.

Two editorials in the same issue of The Lancet added some perspective on the findings of the three studies.

In commenting on the immunogenicity findings, Australian experts Heath Kelly from the Victorian Infectious Disease Reference in Melbourne and Ian Barr from the WHO's collaborating center in Melbourne wrote that the studies build on evidence from other vaccine producers that one dose is enough for healthy adults.

They pointed out, though, that the studies don't all agree on whether adjuvants are an ideal dose-sparing strategy. The U.S. and Hungarian studies show some support for adjuvant use, but the Chinese study suggests that a low-dose unadjuvanted vaccine is preferable for adults.

The three studies cover a range of the healthy population, Kelly and Barr note, but more trials are needed to explore pandemic H1N1 vaccine use in groups that have been more severely affected by the virus, such as pregnant women, native populations and those with underlying conditions such as morbid obesity.

They said that, though the studies suggest one dose is enough to protect adults and two doses are ideal for children younger than 9, countries must still grapple with how to best target their pandemic vaccine supplies.

Addressing the safety aspects of the study were Dina Pfeifer, Claudia Alfonso and David Wood, who are three experts from the quality and safety division of the WHO's vaccine department. They wrote that the three studies are important because they report a body of safety data that was previously seen only by regulators.

They wrote that though randomized trials are valuable, post-marketing surveillance is crucial for detecting rare events. The authors added the adverse events patterns are consistent with those seen for the seasonal flu vaccine, and systemic effects reported among children in the U.S. study are consistent with background rates for respiratory infections in the same age group.

Understanding adverse events with concurrent use of seasonal and pandemic vaccine is useful, the WHO group wrote, and other vaccine combinations are also worthy of safety studies, such as co-administration of pandemic and pneumococcal vaccines.

The three studies support December 2009 WHO advisory group conclusion that so far no unexpected safety concerns have arisen from any pandemic H1N1 vaccine that countries are using in immunization campaigns. However, they reiterated cautions that the world is in a relatively early stage of pandemic vaccination and that ongoing safety monitoring is needed, with rapid reporting of findings.

"The ongoing worldwide safety evaluation of the pandemic H1N1 vaccines is unprecedented and will provide the most documented safety profile of any vaccine in history," the WHO group concluded.