Influenza H1N1 monovalent vaccines – Preliminary reports on efficacy and safety

Background

The recently described influenza A H1N1 2009 virus (2009H1N1), with its global spread, has resulted, in June 2009, with the first declaration by the World Health Organization (WHO) of an influenza pandemia in 41 years.

Influenza and its prevention and treatment has been a major focus in preventive and cardiovascular medicine since 2005, when the influenza virus subtype H5N1 was spread in Europe. In contrast to the H5N1 virus, which is pathogenic primarily for poultry and only rarely causes human infections and deaths, the human influenza A virus infection (subtypes H1N1, H1N2, and H3N2) leads to thousands of deaths each year.

Vaccination with seasonal trivalent inactivated influenza vaccines has been associated with a 50% reduction in all-cause mortality in healthy elderly persons (1). A meta-analysis of 20 cohort studies confirmed a reduction in death rates of 68% (2). Interestingly, in patients with cardiovascular disease, vaccination against influenza was associated with a decreased rate in new onset acute myocardial infarction within the 1997/1998 (3) influenza season. In further studies evaluating 280,000 patients, vaccination against influenza was associated with a risk reduction for hospitalisation due to cardiovascular disease, cerebrovascular disease, and all-cause mortality (4).

The underlying pathophysiological explanations include prevention of systemic inflammation that involve the release of inflammatory cytokines, development of endothelial dysfunction, changes in plasma viscosity, as well as endogenous catecholamines, dehydration, and induction of pro-coagulative activity of infected endothelial cells which may contribute to the development of instable plaques and plaque rupture (5). 

2009 H1N1 Virus Infection – Current status

Data now available derived from the influenza season of the southern hemisphere clearly demonstrate that 2009 H1N1 infections will likely be a public health burden in Europe with substantial increases in the incidence of 2009 H1N1 infection. Between April and August 2009 the proportion of the new influenza reached 60-70%. While recent influenza A virus infections affected mostly the elderly, the 2009 H1N1 virus seems to preferably affect younger people. The mean age in Germany of infected patients is 22.8 years and about 75% of infected patients are between 10 and 29 years of age. Risk factors for a severe form of the influenza are pregnancy and chronic disease e.g. pulmonary and cardiovascular diseases. About 90% of deceased patients due to 2009 H1N1 infection had a previous history of chronic disease (6). 

A recently published article in the New England Journal of Medicine related the information demonstrating that vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1(7).  Interestingly, only 4% of persons who were born after 1980 had pre-existing cross-reactive antibody titers of 1:40 or more against 2009 H1N1, whereas 34% of persons born before 1950 had titers of 1:80 or more. These observations underline the importance of a specific immunisation against the 2009 H1N1 virus.

Meanwhile, two preliminary studies have been published showing promising results concerning the efficacy and safety of monovalent Influenza A H1N1 2009 Vaccine(8;9). The first study comes from Australia and has investigated a monovalent vaccine developed by CSL in a total of 240 healthy subjects. In order to study the different susceptibility against the 2009 H1N1 virus according to age groups, the cohort was divided into two age groups (<50 years and =50 years). Subjects were randomised to receive either a single shot of 15 µg or 30 µg of hemagglutinin antigen by intramuscular injection. The primary endpoints were antibody titers using hemagglutination-inhibition and microneutralisation assays at baseline and 21 days after vaccination.  Antibody titers of 1:40 or more were observed in 96.7% of subjects who received the 15-µg dose and in 93.3% of patients who received the 30-µg dose. Adverse events of the vaccination were comparable to other influenza vaccinations with mild to moderate local discomfort at the injection site (mainly pain and tenderness) in 46.3% and systemic events (mainly headache, malaise, myalgia) in 45%.  No deaths, serious adverse events, or unexpected adverse events were observed suggesting an acceptable safety profile of the vaccine.

The second available study is a single-center study from the UK evaluating the effect of a monovalent influenza A/California/2009 (H1N1) surface-antigen vaccine developed by Novartis in 175 adult subjects in the age of 18 to 50 years. In contrast to the CSL vaccine, an adjuvant as well as a non-adjuvanted form was investigated. The addition of adjuvant is known to enhance immunogenicity and may further induce cross-reactive antibodies against antigenically drifted variants. In order to study dose effects and efficacy of multiple dosing, subjects were randomised to receive either

Antibody responses were measured by means of hemagglutination-inhibition assay and a microneutralization assay on days 0, 14, 21, and 42 after injection of the first dose.

The interim analysis published only compromises group 1 treated with the 7.5-µg dose of MF59-adjuvanted vaccine by days 0, 7, and 14. Here it was shown that antibody titers were significantly higher at day 14 in subjects who had received two 7.5-µg doses of the MF59-adjuvanted vaccine than among those who had received only one by day 14 (Group 1d with a scheduled second dose on day 21). By 21 days after vaccination, the rates of seroconversion were 76% and 92% dependant on the assay used in subjects treated with only one dose (Group 1c) and 88, 92, 88% and 92, 96, 96% in subjects who had already received both doses (Group 1 a-c, respectively). Again, the safety profile of the vaccine was acceptable with frequent local and systemic reactions in 70% and 42% of subjects, respectively.

Conclusion:

• Healthcare providers and all patients with severe medical conditions including patients with chronic heart or lung disease, patients in nursing homes as well as all patients>65 years of age (high risk group) should be immunized with the seasonal trivalent inactivated influenza vaccines.
• There is only little evidence of cross-reactive antibodies against the 2009 H1N1 virus with no evidence of protection from the seasonal influenza.
• Surprisingly, a single dose of vaccine seems to be enough to generate adequate immunity. This may have major implications on public health costs since initial calculations were based on two injections to receive efficient antibody titers.
• Children and young adults seem to be the group most affected by 2009 H1N1. The immunogenicity data are difficult to extrapolate to children or to adults with underlying immune suppression or high-risk concomitant diseases. These populations will probably be a group in whom influenza vaccine is urgently recommended.
• The monovalent 2009 H1N1 vaccine need to be combined with the seasonal trivalent inactivated influenza vaccines.
• The safety profile of the vaccines seems acceptable with only minor to mild adverse events. However, careful surveillance of side effects will be crucial when vaccination will be performed in larger populations.