Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

3rd European Influenza Conference

Vilamoura, Portugal / September 14-17, 2008

According to Dr. Ira M. Longini, Jr., University of Washington, Seattle, if the avian or another zoonotic influenza virus evolves into a form that spreads readily among humans, the optimal approach is containment of the pandemic strain at the source. But if this fails, then the global response must focus on slowing the spread of this strain until a well-matched vaccine can be made and distributed. A “pre-pandemic” vaccine based on existing avian influenza strains (e.g. H5N1) is likely to offer some protection against an emerging pandemic strain until a specific pandemic vaccine can be developed and produced, which the World Health Organization (WHO) predicts could take four to six months.

“In the evidence of a pandemic, physicians must immediately begin mitigating spread if containment fails,” Dr. Longini stated. This response may include the use of antivirals and other medications. “If pre-pandemic vaccine is available in the event of the identification of a beginning influenza pandemic, then physicians should immediately start using it as indicated, with an initial priming injection and a booster injection after 21 days,” he continued. That means that physicians must “be ready and understand how to apply both [medical approaches] in a reactive fashion.”

This is not just a theoretical issue, Dr. Longini warned. “We already have growing evidence of resistance to antivirals [by existing strains of influenza viruses],” explaining that in Norway, up to two-thirds of isolated cases of human infection with H1N1 are already resistant to selected antiviral medications. “It would be prudent for governments to begin stockpiling [pre-pandemic] vaccine now, keeping antigen and adjuvant separate,” he remarked. The reason for separating antigen from adjuvant is to provide flexibility to replace the antigen component in case of antigen drift over time, Dr. Longini explained.

Mathematical Modelling of Pre-pandemic Vaccines

Prof. Neil M. Ferguson, Professor of Mathematical Biology, Division of Epidemiology, Public Health and Primary Care, Imperial College, London, UK, used mathematical modelling to demonstrate the potential effectiveness of vaccinating individuals with a pre-pandemic vaccine. As he explained, current data indicate “the speed of spread of the pandemic globally means we certainly cannot rely on having matched vaccine available for the first wave of a new pandemic.”

Mathematical models predict that immediate vaccination, as soon as a pandemic is identified, could significantly improve containment of the pandemic and help mitigate its impact. Prof. Ferguson’s models assumed vaccination of 1 to 10 million people in the area surrounding the site of the initial outbreak. Positive results were obtained if the theoretical pre-pandemic vaccine had even a low level of protection against the actual pandemic strain of influenza. The effectiveness of immediate vaccination with the pre-pandemic vaccine depended both on the degree to which the standard two-dose vaccination schedule could be accelerated and on the amount of protection provided by a single dose of the vaccine. “We need to add this [immediate vaccination] to existing containment measures,” Prof. Ferguson stated, adding that the best outcomes include this vaccination in addition to, not as a substitute for, antiviral medications and public health interventions to reduce contact rates. “Pre-pandemic vaccine use can potentially and substantially reduce clinical attack rates in a flu pandemic even with relatively low efficacy and only moderate levels of coverage,” he summarized.

Pre-pandemic H5N1 Clade 1 Vaccine

Dr. Albert Osterhaus, Erasmus Medical College, University of Rotterdam, The Netherlands, stressed the need to develop safe, highly immunogenic, antigen-sparing vaccines that can elicit immunity to drifted strains. “[This type of vaccine] should induce strong antibody responses, preferably long-lasting, and it should be broadly reactive.” Broad cross-protective immunity against emergent H5N1 viruses belonging to clades 1 and 2, both of which are associated with human cases of avian influenza infection, is particularly important. (A virus “clade” is a group of viral variants that are closely related.)

Dr. Osterhaus reviewed clinical data obtained with a pre-pandemic vaccine directed against the H5N1 A/Vietnam 1194/2004 (clade 1) influenza strain. This pre-pandemic influenza vaccine is adjuvanted with a novel 10% oil-in-water emulsion-based adjuvant system (AS03). Two doses of the H5N1 clade 1-containing vaccine given 21 days apart induced an immune response against the vaccine strain in healthy volunteers aged 18 to 64 years. Vaccination also promoted cross-immunity against a recent clade 2 H5N1 isolate (A/Indonesia/5/2005, subclade 2.1) and showed some cross-protective potential against examples of WHO subclades 2.2 and 2.3.

Including the adjuvant in the vaccine allowed the use of a smaller amount of antigen. Formulation with 3.8 µg hemagglutinin antigen in adjuvanted vaccines induced a high level of hemagglutination inhibition and neutralizing antibodies, Dr. Osterhaus indicated. He added, “Antigen-sparing capacity [is] a very important point because our vaccine capacity worldwide for the next pandemic vaccine is limited.”

Preclinical studies in a proven ferret model allowed researchers to directly test the ability of the vaccine to protect against subsequent infection with highly pathogenic H5N1 virus, a trial that cannot be performed in humans. The vaccinated models had higher rates of survival and reduced viral load in lung tissue samples compared with those in a control group. Only 30% of the vaccinated ferrets shed virus, another important consideration that, if also true in humans, may mean a significant reduction in the transmission of influenza virus in a pandemic.

The vaccine has also been evaluated in children 3 to 9 years of age and was found to have an acceptable safety and reactogenicity profile in this group.

Clinical Data: H5N1 Clade 2 Vaccines

Dr. Joanne Langley, Dalhousie University, and IWK Health Centre, Halifax, Nova Scotia, described safety and cross-reactive immunogenicity results from a recently completed phase I/II clinical trial of candidate clade 2 vaccines in adults. Most clinical trials have evaluated vaccines against clade 1 strains of H5N1, which infected humans in 2004-2005, but clade 2 strains are known to have infected humans beginning in 2005. This trial evaluated two H5N1 A/Indonesia/5/2005 (clade 2.1) AS03-adjuvanted vaccine candidates and compared them with nonadjuvanted vaccine.

Adults aged 18 to 64 years received two doses of vaccine, 21 days apart, containing 3.75 µg hemagglutinin antigen either with AS03 adjuvant (150 participants) or without adjuvant (control group, 75 participants). Evaluation of safety data, including local and general symptoms, adverse events (AEs) and serious AEs, revealed more frequent injection-site pain in those receiving the adjuvanted vaccine compared with control, but redness and swelling occurred in <5% of participants. No vaccine-related serious AEs were reported. After one dose, clade 2.1 seroconversion rates were 42.1% to 45.7% in the adjuvanted vaccine groups (control group, 6.7%). After the second dose, seroconversion rates reached 96.4% to 97.2% in the adjuvanted vaccine group, compared with 17.3% in the control group. Vaccination with the adjuvanted vaccine also led to protection against the clade 1 influenza strain; seroconversion after two doses was 56.4% to 62.1%. As Dr. Langley summarized, the results demonstrate markedly increased seroconversion in the group receiving adjuvanted vaccines compared to nonadjuvanted vaccine.

Preparation of Candidate Pandemic Vaccines

In a second presentation, Dr. Osterhaus discussed logistical problems with the development of matched pandemic vaccines but pointed out some significant progress that has been made in these areas. Some of the uncertainties that countries face today when planning their responses to a potential pandemic include the efficacy of any stockpiled pre-pandemic vaccines against a new pandemic strain, the response time to create a vaccine matched to the pandemic strain and the capability of worldwide vaccine manufacturing to rapidly scale up and produce sufficient quantities of matched vaccine. Fortunately, newer techniques in vaccine development have led to vaccines with broader and longer-lasting protection. Procedures that enhance immune response mean that less antigen is required for vaccines, which, in turn, eases some of the production concerns. In addition, once scientists identify the early signs of a pandemic and isolate the virus, they can use newer molecular techniques such as reverse genetics to more rapidly produce a matched vaccine. Scientists are also developing and constantly updating stores of “seed viruses” from the ever-changing reservoirs of avian influenza viruses for use in potential pandemic vaccines. Global vaccine production capacity has increased as well.

Summary

Pre-pandemic vaccines directed against the H5N1 influenza virus offer an important additional tool for responding to a pandemic when used in conjunction with other medicines and containment approaches. They are particularly crucial given the time required to produce a new matched vaccine in the event of an outbreak of pandemic virus. An adjuvanted vaccine against H5N1 A/Vietnam 1194/2004 (clade 1) influenza has been shown safe and effective in clinical trials and provides cross-immunity against a recent clade 2 virus. Other candidate vaccines have been developed and tested, including two adjuvanted vaccines against a more recent H5N1 clade 2.1 influenza strain. These produced seroconversion rates of 42.1% to 45.7% after one dose and 96.4% to 97.2% after two doses, with good cross-reactive immunogenicity against an older clade 1 strain.