Three H1N1 vaccine studies confirm safety, weigh dosing

Jan 4, 2010 (CIDRAP News) – Large trials in three countries—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.

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.

For example, in the US study, even the lowest of three doses studied—7.5 micrograms (mcg) of antigen—produced a strong response in adults, but the findings suggest younger children likely need two doses. And in the Hungarian study, coadminstration of pandemic and seasonal flu vaccines was safe and effective.

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 (WHO) experts.

US findings confirm vaccine strategy
The US study consisted of two phase 2 trials of Sanofi'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). Adults received one of three antigen doses 7.5, 15, or 30 mcg, while children received either 7.5- or 15-mcg doses. Researchers enrolled participants from 35 clinical sites, representing 18 states.

The investigators took serum samples before and 21 days after vaccination. Participants or their parents kept safety diaries for 7 days after immunization.

Adults of both age-groups showed a strong immune response to all vaccine doses, but the response was higher in those younger than 65. Seroprotection rates ranged from 93% to 100%. After 21 days, immune response to the vaccine in children was lower than for adults.

Injection-site pain and tenderness was the most frequent reaction reported in all groups, and the rates of systemic reactions were about the same in the vaccine and placebo groups.

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 US Food and Drug Administration's (FDA'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.

Cross-reactive immune response was higher in adults who had received their seasonal flu vaccine in the five previous seasons, but they're not sure if seasonal immunization or some other factor, such as exposure to similar influenza strains, could have contributed to the baseline response pattern they observed. However, they didn't see a greater response to the pandemic virus among people born before 1957 who may have been exposed to other H1N1 subtypes.

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.

Hungarians compare seasonal, H1N1 vaccines
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 prepandemic 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.

Investigators tested participants' serum before vaccine administration and at 21 days after immunization. They collected safety information by phone 1, 2, 3, and 7 days after vaccination, as well as during follow-up visits. Subjects were also asked to take their temperatures on days 1, 2, and 3 and to record any side effects on diary cards.

Adverse events were mild and similar to seasonal flu vaccine, mostly appearing the day after immunization and resolving by the second or third day. No difference in local reaction was noted between groups that received just the pandemic vaccine and groups that received both at the same time.

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.

Baseline testing showed little preexisting protection against the pandemic strain, which they said might be partly explained by very little pandemic H1N1 activity in Hungary in August 2009 when trial was conducted.

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 coadministration is safe and effective is useful for pandemic planners who must manage vaccine logistics.

Also, they wrote that the favorable efficacy of a 6-mcg adjuvanted vaccine is useful for setting dose-sparing strategies in a pandemic setting when vaccine supply falls short of demand. Vaccines approved in the United States, for example, contain 15 mcg of antigen per dose.

Chinese study tests multiple formulations
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 unadjuvanted 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.

Serum samples were obtained at baseline, at 21 days (before the second dose was given), and at 21 days after the second dose. Some centers also took serum samples 14 days after the second dose.

Researchers observed participants for 30 minutes after vaccination and asked subject to use diary cards for the next 3 days to record any adverse events.

Seroprotection at day 21 ranged from 69.5% for the adjuvanted 7.5-mcg split-virus formulation to 92.8% for the unadjuvanted 30-mcg split-virus pandemic vaccine.

Protection after one dose 7.5-mcg dose of the unadjuvanted split-virus vaccine was 86.5%. The same vaccine met European Union protection requirements for licensing for all age-groups that were studied, but a second dose in children boosted seroprotection to 97.7%.

All eight formulations from the 10 research sites were well tolerated, the investigators reported. Severe adverse events occurred in 69 vaccine recipients, compared with one who received placebo. The most common was fever, which occurred in 25 participants.

Detectable baseline antibody titers were seen in 17.8% of the vaccine group and 19% of the placebo group. Levels were lower in children, but did not vary significantly between the other age-groups.

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 antigen, which could be useful during a pandemic when vaccine is in short supply. However, they added that children ages 3 to 12 may 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.

Experts: studies reassuring, but questions remain
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 US 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 three experts from the quality and safety division of the WHO's vaccine department, Dina Pfeifer, Claudia Alfonso, and David Wood. 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, postmarketing 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 US 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 coadministration 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.

Plennevaux E, Sheldon E, Blatter M, et al. Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of two randomized controlled phase 2 trials. Lancet 2010 Jan 2;375(9708):41-8 [Full text]

Vajo Z, Tamas F, Sinka L, et al. Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with seasonal influenza vaccine for the 2009-10 influenza season: a multicentre, randomized controlled trial. Lancet 2010 Jan 2;375(9708):49-55 [Full text]

Liang X-F, Wang H-Q, Wang J-Z, et al. Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomized, placebo-controlled trial. Lancet 2010 Jan 2;375(9708):56-66 [Full text]

Kelly H, Barr I. Large trials confirm immunogenicity of H1N1 vaccines. (Editorial) Lancet 2010 Jan 2;375(9708):6-8 [Full text]

Pfeifer D, Alfonso C, Wood D. Defining the safety profile of pandemic influenza vaccines. (Editorial) Lancet 2010 Jan 2;375(9708):9-11 [Full text]

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