Three articles published Online First and in an upcoming edition of The Lancet report the conclusions of three studies from the USA, China, and Hungary. They show that one dose of H1N1 influenza vaccine should give adults sufficient protection from infection. Two doses could be required for children aged under 9 years in the USA study or under 12 years for the Chinese study.

To find the correct antigen dose and vaccination schedule to protect against 2009 pandemic influenza A H1N1, information is needed from large clinical trials in children, adults, and elderly people. The three studies report preliminary safety and immunogenicity results after administration of pandemic H1N1 vaccines in these three countries.

The first article documents the USA study. It is the work of Dr Martine Denis, Sanofi-Pasteur, Lyon, France, and colleagues. This study reviewed the immune response generated by a vaccine approved by the US Food and Drug Administration. The manufacturer is Sanofi-Pasteur, PA, USA. This vaccine was produced in accordance with the process used to produce a regular seasonal influenza vaccine, as per WHO recommendations.

This preliminary report included two randomized controlled phase 2 trials. The participants were healthy children aged 6 to 35 months and 3 to 9 years and adults 18 to 64 years and 65 years and over. They were randomized to vaccine containing, per dose 7•5 μg (children and adults), 15 μg (children and adults), or 30 μg (adults only) haemagglutinin. Haemagglutinin is a protein on the flu virus surface used as an antigen to stimulate immune-reaction against the virus.

The research team evaluated 410 of 423 children and 724 of 750 who were given an active vaccine. 50 of 51 children and 95 of 99 adults were given placebo for immunogenicity on day 21. After active vaccination, between 45 percent (7•5 μg dose) and 50 percent (15 μg) infants aged 6 to 35 months were seroprotected. The matching figures for the other age groups were 69 percent (7•5 μg) to 75 percent (15 μg) of 3 to 9-year-old children; 95 percent (7•5 μg) to 100 percent (30 μg) of 18 to 64-year-old adults; and 93 percent (15 μg) to 95 percent (30 μg) of elderly adults. There were no reports of vaccine-related serious adverse events. Injection-site and systemic reactions were reported by up to about 50 percent of every age and vaccine group. There were no noticeable differences between vaccine and placebo groups.

The authors write in conclusion: “One dose of vaccine was highly immunogenic in adults, suggesting that it afforded sufficient protection against this pandemic influenza A H1N1 virus. 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… These preliminary results also show that a substantial proportion of children are already seroprotected after their first vaccination. We will report the immunogenicity and safety of a two-dose vaccination schedule in children as soon as all the study results are available.”

The second article reports the China study. It was written by Dr Yu Wang, Chinese Centre for Disease Control and Prevention, Beijing, China, and colleagues. The randomized, placebo-controlled study recruited participants in ten centres in China. It included 12,691 people aged 3 years or older and assessed eight vaccine formulations.

The researchers found that seroprotection rates varied from 70 percent to 93 percent. This depended on the formulation used with the 30 μg non-adjuvant formula giving the best protection. An adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself. As with the USA study, the 7.5 μg, non-adjuvant formula offered substantial seroprotection. It was 87 percent across all age groups protected compared to 10 percent for placebo. In terms of individual age groups, this 7.5 μg formulation induced seroprotection in 77 percent of children aged 3 to12 years; 97 percent of adolescents aged 12 to18 years; 90 percent of adults aged 18 to 60 years; and 80 percent of adults aged over 60 years. In children aged 3 to12 years, a second dose of this same 7.5 μg formulation increased seroprotection rates to 98 percent.

Most of the adverse reactions were mild or moderate, and self-limited. Severe adverse events occurred in 69 (0•6 percent) recipients of vaccine compared with one recipient (0•1 percent) of placebo. Fever was the most common severe adverse reaction. It occurred in 25 (0•22 percent) recipients of vaccine after the first dose and four (0•04 percent) recipients of vaccine after the second dose compared with no recipients of placebo after either dose.

The authors say in closing: “We recommend that non-adjuvant split-virion vaccine containing 7•5 μg haemagglutinin is adopted as the vaccine of choice against 2009 pandemic H1N1 in adolescents and adults. A two-dose schedule of this formulation might be needed in children.”

The third article informs on the study in Hungary. It was written by Professor Zoltan Vajo, University of Debrecen, Hungary, and colleagues. This randomized controlled study investigated the administration of a pandemic H1N1 vaccine both alone and together with the regular seasonal influenza vaccine.

There were a total of 355 participants, including 203 adults (18 to 60 years) and 152 elderly people (over 60 years). There were two groups:

• Group 1: 0•5 mL of the pandemic vaccine (Fluval P, a monovalent vaccine with 6 μg haemagglutinin per 0•5 mL and aluminium phosphate gel adjuvant); 178 recipients.

• Group 2: 0•5 mL of the pandemic vaccine and 0•5 mL of the regular trivalent seasonal influenza vaccine; 177 recipients.

Findings indicated that participants in both groups developed antibody responses against the pandemic influenza A H1N1 virus:

• Group 1: seroprotection rate for adults 74 percent, and for elderly people 61 percent.

• Group 2: 76•8 percent, and 81•8 percent, respectively.

Single doses of 6 μg fulfilled European Union and US licensing criteria for both the combined and H1N1 pandemic only vaccines. At the same time, participants in group 2 developed the immune responses needed for licensing for all three strains in the seasonal vaccine for the 2009-10 season. All adverse events were rare, mild, and transient. Pain at injection site was the most frequent (eight cases in group 1 compared to 18 in group 2) and fatigue for 1 to 2 days after vaccination (three compared to five cases).

The authors write in conclusion: “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 licensing criteria. 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.” In Hungary, the H1N1 vaccine is being administered alone in some cases and together with the seasonal flu vaccine in other cases.

In an associated note, Dr Heath Kelly, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia, and Dr Ian Barr, WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, Australia, remark: “Although today’s three trials cover a wide age range of the healthy population, subgroups who have been more severely affected by pandemic H1N1 – pregnant women, indigenous people, the morbidly obese, and those with underlying co-morbidities-have not been included in trials to date. These are considered priority groups for vaccination in many countries, and postmarketing surveillance should include vaccine-effectiveness studies in these groups. 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.”

They conclude: “The first influenza pandemic of the 21st century has raised many questions about our understanding of the epidemiology of both seasonal and pandemic influenza. 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.”

In a second commentary on the three studies, Dr Dina Pfeifer, Quality, Safety and Standards, Department of Immunization, Vaccines and Biologicals, WHO, Geneva, Switzerland, and colleagues observe: “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. 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.”

“Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of two randomised controlled phase 2 trials”
Eric Plennevaux, Eric Sheldon, Mark Blatter, Mary-Kate Reeves-Hoché, Martine Denis
DOI: 10.1016/S0140-6736(09)62026-2
The Lancet

Written by Stephanie Brunner (B.A.)