Single Dose of H1N1 Vaccine Needed for Adults, 2 for Children

December 15, 2009 — One dose of 2009 pandemic influenza A (H1N1) vaccine should be sufficiently protective in adults, whereas 2 doses could be required in children, according to the results of 3 randomized controlled trials reported online December 16 in The Lancet. Two accompanying commentaries discuss the clinical implications of these studies, which were conducted in the United States, China, and Hungary.

The purpose of these large clinical trials inadults, older adults, and children was to determine the appropriate antigen dose and vaccination schedule to protect against pandemic H1N1 influenza infection. The 3 studies report preliminary safety and immunogenicity results after administration of pandemic H1N1 vaccines.

Although findings from the US study suggest that children younger than 9 years may require 2 doses of H1N1 influenza vaccine for optimal protection against infection, investigators from the Chinese study drew similar conclusions regarding children younger than 12 years. In both of these studies, the 7.5-μg, nonadjuvant formula offered substantial seroprotection (87% across all age groups in the Chinese study vs 10% for placebo). Adverse effects were mostly mild and self-limited.

The Hungarian study evaluated a whole-virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine in adults and elderly adults only. Safety and immunogenicity of the H1N1 vaccine were good in both age groups, whether given alone or simultaneously with seasonal influenza vaccine.

“The first influenza pandemic of the 21st century has raised many questions about our understanding of the epidemiology of both seasonal and pandemic influenza,” Heath Kelly, MBBS, MPH, from the Victorian Infectious Diseases Reference Laboratory, and Ian Barr, PhD, from the World Health Organization Collaborating Centre for Reference and Research on Influenza, both in Melbourne, Australia, write in an accompanying comment.

“In view of the standard regulatory criteria for influenza vaccines, preliminary trial results suggest one dose of vaccine against pandemic H1N1 will be adequate for healthy adults of all ages, while children younger than 9 years may need two doses. However, the optimum use of a pandemic vaccine remains an unanswered question,” they point out.

US Study

The US study, by Eric Plennevaux, PhD, from Miami Research Associates in Florida, and colleagues, evaluated the immune response elicited by H1N1 vaccine manufactured by Sanofi Pasteur in accordance with World Health Organization recommendations for production of a seasonal influenza vaccine and approved by the US Food and Drug Administration (FDA).

In 2 placebo-controlled, observer-blinded, US multicenter phase 2 trials, healthy children (6 – 35 months and 3 – 9 years of age) and adults (18 – 64 years of age and 65 years or older) were randomly assigned to receive vaccine containing 7.5 or 15 μg hemagglutinin per dose (in children and adults), or 30 μg hemagglutinin per dose (in adults only).

In this preliminary interim analysis of ongoing studies, the main study endpoint was hemagglutination inhibition antibody response 21 days after the first of 2 planned vaccinations. This outcome was measured in 410 of 423 children and 724 of 750 adults given active vaccine, and in 50 of 51 children and 95 of 99 adults given placebo.

Seroprotection, defined as titers ≥1:40, occurred in 45% to 50% of infants aged 6 to 35 months, in 69% to 75% of children aged 3 to 9 years, in 95% to 100% of adults aged 18 to 64 years, and in 93% to 95% of elderly adults. Up to about 50% of every age and vaccine group had injection-site and systemic reactions, but there were no apparent differences between vaccine and placebo groups and no vaccine-related serious adverse events.

“One dose of vaccine was highly immunogenic in adults, suggesting that it afforded sufficient protection against this pandemic influenza A H1N1 virus,” the study authors write. “Two doses of vaccine will probably be needed in children younger than 9 years. Safety and reactogenicity of the vaccine were acceptable and similar to those of seasonal vaccine.”

Although a substantial proportion of children are already seroprotected after 1 dose, the study authors plan to report the immunogenicity and safety of a 2-dose vaccination schedule in children as soon as all the study data are obtained.

Chinese Study

The Chinese study, by Xiao-Feng Liang, MD, from the Chinese Centre for Disease Control and Prevention in Beijing, and colleagues, was a double-blind trial of pandemic influenza A (H1N1) vaccine produced by 10 Chinese manufacturers. At 10 centers, 12,691 people aged 3 years or older were recruited, stratified by age, and randomly assigned to receive placebo or 1 of 8 vaccine formulations produced from the reassortant strain X-179A (A/California/07/2009-A/PR/8/34): split-virion formulation containing 7.5, 15, or 30 μg hemagglutinin per dose, with or without aluminum hydroxide adjuvant, and whole-virion formulation containing 5 or 10 μg hemagglutinin per dose, with adjuvant. Of 12,691 participants who received the first dose on day 0, 12,348 participants received the second dose on day 21.

At 21 days after the first vaccine dose, the seroprotection rate ranged from 69.5% for the 7.5-μg adjuvant split-virion formulation to 92.8% for the 30-μg nonadjuvant split-virion formulation. Seroprotection was 86.5% in those who received 1 dose of 7.5-μg nonadjuvant split-virion vaccine vs 9.8% in those who received placebo (P < .0001). In all age groups, 1 dose of 7.5-μg nonadjuvant split-virion vaccine met the European Union’s licensure criteria for seroprotection and was protective in 76.7% of children aged from 3 years to younger than 12 years, in 96.8% of adolescents aged 12 years to younger than 18 years, in 89.5% of adults aged 18 to 60 years, and in 80.3% of adults older than 60 years. A second dose of the 7.5-μg formulation increased the seroprotection rate in children to 97.7%.

Although most adverse reactions were mild or moderate and self-limited, severe adverse effects occurred in 0.6% of vaccine recipients and in 0.1% of placebo recipient. Fever was the most common severe adverse reaction, reported in 0.22% of vaccine recipients after the first dose and in 0.04% of vaccine recipients after the second dose vs in none of the placebo recipients after either dose.

“One dose of non-adjuvant split-virion vaccine containing 7.5 μg haemagglutinin could be promoted as the formulation of choice against 2009 pandemic influenza A H1N1 for people aged 12 years or older,” the study authors write. “In children (aged <12 years), two 7.5 μg doses might be needed.”

Hungarian Study

In the Hungarian study, Zoltan Vajo, from University of Debrecen, and colleagues evaluated the safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009 to 2010 influenza season. At 2 centers in Hungary, this prospective, randomized trial enrolled 203 adults aged 18 to 60 years and 152 adults older than 60 years. Using stratified randomization, participants were assigned to receive either 0.5 mL of Fluval P (Omninvest), a monovalent vaccine with 6 μg hemagglutinin per 0.5 mL content and aluminum phosphate gel adjuvant, or 0.5 mL of the pandemic vaccine and 0.5 mL of the seasonal trivalent vaccine (Fluval AB, Omninvest; a trivalent inactivated whole-virion influenza vaccine).

For participants receiving the H1N1 vaccine only, seroconversion rates were 74.3% for adults aged 18 to 60 years and 61.3% for those older than 60 years. For those receiving both vaccines, seroconversion rates were 76.8% and 81.8%, respectively, achieving immune responses needed for licensing for all 3 seasonal strains in the seasonal vaccine for the 2009–2010 season. Adverse events were rare, mild, and transient, with the most frequent being injection-site pain and fatigue lasting 1 to 2 days after vaccination.

“The present pandemic vaccine is safe and immunogenic in healthy adult and elderly patients, and needs low doses and only one injection to trigger immune responses to comply with [European Union and US] licensing criteria,” the study authors write. “It can be safely co-administered with the 2009–10 seasonal influenza vaccine…. On the basis of these results, the pandemic H1N1 influenza vaccine presented in this study has been licensed in Hungary, and vaccinations were started on Sept 28, 2009.”

At-Risk Subgroups Not Studied

A limitation of all 3 studies noted by Mr. Kelly and Dr. Barr is their failure to include subgroups who have been more severely affected by pandemic H1N1: pregnant women, indigenous people, morbidly obese patients, and those with underlying comorbidities.

“These are considered priority groups for vaccination in many countries, and postmarketing surveillance should include vaccine-effectiveness studies in these groups,” the authors write. “Moreover, all countries with access to vaccine will need to decide whether a targeted or universal vaccine campaign will be the optimum as a public health policy.”

In a second comment, Dina Pfeifer, MD, from Quality, Safety and Standards, Department of Immunization, Vaccines and Biologicals, World Health Organization, in Geneva, Switzerland, and colleagues, note that critical assessment of the safety profile of vaccines manufactured to respond to the 2009 H1N1 influenza pandemic is of the greatest priority.

“The ongoing world-wide safety evaluation of pandemic H1N1 vaccines is unprecedented and will provide the most documented safety profile of any vaccine in history,” Dr. Pfeifer and colleagues write. “The available data show that pandemic H1N1 vaccines are immunogenic and have an acceptable safety profile. They provide an important public health tool to minimise further harm from the virus.”

The US study was funded by the Office of the Assistant Secretary for Preparedness and Response, and by the Biomedical Advanced Research and Development Authority. Three of the study authors are employees of Sanofi Pasteur. Some of the other study authors report various financial relationships with Sanofi Pasteur, Novartis, GlaxoSmithKline, MedImmune, Wyeth, Merck Sharp and Dohme, and/or Commonwealth Serum Laboratories. The Chinese study was funded by Sinovac Biotech, Hualan Biological Bacterin, China National Biotec Group, Beijing Tiantan Biological Products, Changchun Institute of Biological Products, Changchun Changsheng Life Sciences, Jiangsu Yanshen Biological Technology Stock, Zhejiang Tianyuan Bio-Pharmaceutical, Lanzhou Institute of Biological Products, Shanghai Institute of Biological Products, and Dalian Aleph Biomedical. Vaccine manufacturers employ 11 of the study authors and have various financial relationships with 7 other study authors. Omninvest funded the Hungarian study. The study authors and commentators have disclosed no relevant financial relationships.

Lancet. Published online December 16, 2009.

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