H1N1 vaccine effectiveness and safety: 1 dose needed for adults, 2 for children

December 15, 2009

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

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

The first Article (USA study) was written by Dr Martine Denis, Sanofi-Pasteur, Lyon, France, and colleagues. This study looked at the immune response generated by a vaccine approved by the US Food and Drug Administration (manufacturer: 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.

In this preliminary report of two randomised controlled phase 2 trials, healthy children (aged 6󈞏 months and 3𔃇 years) and adults (18󈞬 years and ≥65 years) were randomised to vaccine containing, per dose 7•5 μg (children and adults), 15 μg (children and adults), or 30 μg (adults only) haemagglutinin*.

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

The authors conclude: "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 (China) was written by Dr Yu Wang, Chinese Centre for Disease Control and Prevention, Beijing, China, and colleagues. The randomised, placebo-controlled study recruited 12 691 people aged 3 years or older were recruited in ten centres in China, and assessed eight vaccine formulations.

The research team found that seroprotection rates varied from 70% to 93% depending on the formulation used (with the 30 μg non-adjuvant** formula giving the best protection). As with the USA study, the 7.5 μg, non-adjuvant formula offered substantial seroprotection--with 87% across all age groups protected (vs 10% for placebo). In terms of individual age groups, this 7.5 μg formulation induced seroprotection in 77% of children aged 3--12 years; 97% of adolescents aged 12--18 years; 90% of adults aged 18--60 years; and 80% of adults aged over 60 years. In children aged 3--12 years, a second dose of this same 7.5 μg formulation increased seroprotection rates to 98%.

Adverse reactions were mostly mild or moderate, and self-limited. Severe adverse eventsoccurred in 69 (0•6%) recipients of vaccine compared with one recipient (0•1%) of placebo. The most common severe adverse reaction was fever, which occurred in 25 (0•22%) recipients of vaccine after the first dose and four (0•04%) recipients of vaccine after the second dose compared with no recipients of placebo after either dose.

The authors conclude: "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 (Hungary) was written by Professor Zoltan Vajo, University of Debrecen, Hungary, and colleagues. This randomised controlled study looked at administration of a pandemic H1N1 vaccine both alone and together with the regular seasonal influenza vaccine.

A total of 355 participants, including 203 adults (18󈞨 years) and 152 elderly people (>60 years), were assigned to either 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 1) or 0•5 mL of the pandemic vaccine and 0•5 mL of the regular trivalent seasonal influenza vaccine; 177 recipients--group 2.

The researchers found that participants in both groups developed antibody responses against the pandemic influenza A H1N1 virus (group 1: seroprotection rate for adults 74%, and for elderly people 61%; group 2: 76•8%, and 81•8%, respectively). Single doses of 6 μg fulfilled European Union and US licensing criteria for both the combined and H1N1 pandemic only vaccines. Simultaneously, participants in group 2 developed the immune responses needed for licensing for all three strains in the seasonal vaccine for the 2009 season. All adverse events were rare, mild, and transient; the most frequent were pain at injection site (eight cases in group 1 vs 18 in group 2) and fatigue for 1𔃀 days after vaccination (three vs five cases).

The authors conclude: "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 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 an accompanying Comment, 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, say: "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 Comment accompanying the three studies, Dr Dina Pfeifer, Quality, Safety and Standards, Department of Immunization, Vaccines and Biologicals, WHO, Geneva, Switzerland, and colleagues say: "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."
For Dr Martine Denis, Sanofi-Pasteur, Lyon, France, please contact Donna Carey, Sanofi-Pasteur US Media Relations T) +1 570 957 0717 E) donna.cary@sanofipasteur.com / martine.denis@sanofipasteur.com

Dr Yu Wang, Chinese Center for Disease Control and Prevention, Beijing, China. (China study) T) +86-10-58900301 E) wangyu@chinacdc.cn

Professor Zoltan Vajo, University of Debrecen, Hungary. (Hungary study) T) +36 70 948 9731 E) zoltanvajo@gmail.com

Dr Heath Kelly, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia. T) +61 3 9342 2608 / +61 3 9342 2636 E) heath.kelly@mh.org.au

Dr Dina Pfeifer, Quality, Safety and Standards, Department of Immunization, Vaccines and Biologicals, WHO, Geneva, Switzerland. T) +41-22-791-5000 E) pfeiferd@who.int

For all three Articles and both Comments, see: http://press.thelancet.com/h1n1vaccines.pdf

Notes to editors:

* haemagglutinin is a protein on the flu virus surface used as an antigen to stimulate immune-reaction against the virus.

**Adjuvant: 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

***In Hungary, the H1N1 vaccine is being administered alone in some cases and together with the seasonal flu vaccine in other cases


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