Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Influenza H5N1 vaccines
Pandemrix (GlaxoSmithKline), Panvax (CSL) and Emerflu (Sanofi Pasteur)
multi-dose vials containing suspension for injection
Approved indication: prevention of pandemic H5N1 influenza
Australian Medicines Handbook section 20.1
The avian influenza A virus subtype H5N1 predominantly infects wild birds and poultry. Although rare, humans can contract the infection through close contact with infected birds, and there have been isolated reports of human-to-human transmission. The overall case fatality rate in humans is around 60%. It is feared that the virus could evolve to spread more easily from person to person and cause a pandemic. These vaccines have been approved by the Therapeutic Goods Administration but are only intended to be used once a H5N1 influenza pandemic has been declared. They are all 'mock-up' vaccines based on the prototype H5N1 Vietnam/1194/2004 NIBRG-14 strain. The pandemic strain will only be included in these vaccines once a pandemic occurs.
These are split-virus inactivated vaccines composed of purified antigen fractions from a recombinant virus (which is propagated in fertilised hen eggs) containing the haemagglutinin gene of the prototype strain. The GlaxoSmithKline vaccine contains 3.75 microgram of haemagglutinin per dose with an oil-water emulsion adjuvant (AS03), and the CSL vaccine contains 30 microgram of haemagglutinin per dose with aluminium phosphate as an adjuvant. The Sanofi Pasteur vaccine contains 30 microgram of haemagglutinin per dose mixed with an adjuvant aluminium hydroxide. The vaccines should be given intramuscularly in two doses, three weeks apart.
In a trial of the GlaxoSmithKline vaccine, 86% (42 of 49) of immunised adults had seroconverted or had a significant increase in neutralising antibodies to the vaccine strain 21 days after the second vaccine dose. Similarly, 82% (41 of 49) had antibody titres of at least 1:40 in a haemagglutination-inhibition assay this assay quantifies the highest dilution of patient sera that is able to block haemagglutination of red blood cells by H5N1 virus. In addition, up to 77% of the vaccinees produced neutralising antibodies to another prototype vaccine strain based on influenza A strain H5N1 Indonesia/5/2005, clade 2. Injection-site reactions such as pain, induration and swelling were the most commonly reported adverse events (90%, 28% and 20% of people), most of which were of mild to moderate intensity. Headache, fatigue and muscle aches were also common complaints.1
The CSL vaccine has been assessed in a phase II trial of 400 adults who were given a 30 or 45 microgram haemagglutinin dose. After the second dose, almost 60% of the vaccinees had antibody titres of at least 1:32 in a haemagglutination-inhibition assay.2 There have also been trials of this vaccine in children (6 months to nine years) and the elderly (65 years and older). After the second dose, 98.3% of children and 47.5% of the older adults had seroconverted or had a significant increase in antibody titres to the H5N1 virus. The most common adverse events in adults (reported by 10% of people or more) included headache, nausea, myalgia, fatigue and injection-site reactions. In a phase I trial of this vaccine, a woman had a miscarriage after the second vaccine dose 11 weeks into her pregnancy. This was thought to be possibly related to the vaccine.2 In children, the most common events were headache, decreased appetite, rhinorrhoea, sneezing, diarrhoea, vomiting, myalgia, irritability, fever and injection-site reactions.
The Sanofi Pasteur vaccine was assessed in 51 adults who were given the 30 microgram dose vaccine with adjuvant. After the second dose, 67% of vaccinees had antibody titres of at least 1:32 in a haemagglutination-inhibition assay. A similar proportion had seroconverted or had a significant increase in antibody titres. Three-quarters of the vaccinees had an injection-site reaction these included pain, erythema and induration. Headache (61% of people), myalgia (37%) and malaise (20%) were also common after vaccination.3
It is not known if antibodies produced to these H5N1 vaccines would protect humans from infection. However in a preclinical study of the GlaxoSmithKline vaccine, immunisation protected 22 of 23 ferrets against lethal challenge with a heterologous Indonesian prototype vaccine strain.4
Based on the trials, it seems that two doses are needed to produce a robust antibody response to these H5N1 vaccines in healthy adults. Most people in the trials did not have antibodies to the vaccine strain before they were immunised.1-3 Direct comparison of the immunogenicity data between trials is not really possible as immunoassays, such as the haemagglutination-inhibition assay, may vary between laboratories.
It is important to remember that the safety and efficacy of these prototype vaccines will only be determined during a pandemic once the vaccines have been made. In the event of a pandemic, it will take at least 3-6 months before vaccines such as these are ready for use.5
manufacturer did not respond to request for data (GlaxoSmithKline)
manufacturer declined to supply data (CSL)
Manufacturer provided the clinical evaluation (Sanofi Pasteur)
Notes on references
At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).
- Leroux-Roels I, Borkowski A, Vanwolleghem T, Dramé M, Clement F, Hons E, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007;370:580-9.
- Nolan TM, Richmond PC, Skeljo MV, Pearce G, Hartel G, Formica NT, et al. Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults. Vaccine 2008;26:4160-7.
- Bresson JL, Perronne C, Launay O, Gerdil C, Saville M, Wood J, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 2006;367:1657-64.
- Baras B, Stittelaar KJ, Simon JH, Thoolen RJ, Mossman SP, Pistoor FH, et al. Cross-protection against lethal H5N1 challenge in ferrets with an adjuvanted pandemic influenza vaccine. PLoS ONE 2008;3:e1401.
- Booy R, Brown LE, Grohmann GS, MacIntyre CR. Pandemic vaccines: promises and pitfalls. Med J Aust 2006;185:S62-5