6th WHO Meeting on Evaluation of Pandemic Influenza Vaccines in Clinical Trials, 18-19 February 2010, Geneva

On February 17-18, 2010, the World Health Organization (WHO) convened the 6th meeting on the “Evaluation of pandemic influenza vaccines in clinical trials” to review the progress made on new A (H1N1) 2009 vaccines and prototype H5N1 vaccines and their evaluation in clinical trials. A number of vaccine types were reviewed, including classical egg-derived and cell culture-derived inactivated vaccines, including split virus or whole-virion vaccines, live-attenuated vaccines (LAIV) and vaccines developed using new technologies. The amount of antigen needed, the effect of adjuvants and the number of doses required to induce adequate antibody responses in various populations, together with the issue of safety of the vaccines, were major topics of the meeting. The effectiveness of H1N1 vaccines and the need for standardization of vaccine potency tests were also discussed.

 The production, clinical testing and licensure of pandemic A (H1N1) 2009 vaccines in a limited amount of time was a remarkable achievement of the year 2009, which was fostered in part by close cooperation between the WHO, National Health Authorities and the vaccine industry from both industrialized and developing countries. The development of pandemic H1N1 vaccines was also made easier and faster by the existence of the fast-track system of registration that had been developed in the perspective of an eventual H5N1 influenza pandemic. It nevertheless took several months to have H1N1 vaccines available, so that no vaccination was possible during the 2009 winter season in the Southern Hemisphere when the new virus was prevalent.

All vaccines were well tolerated and elicited only mild or moderate transient side effects, such as local pain, swelling and redness, temporary fever, headache, fatigue or myalgia, including in infants and young children and in pregnant women. Only one severe adverse event was reported among the several thousand children and adults who participated in these trials. The overall safety of the pandemic H1N1 vaccines has since been confirmed during the large-scale vaccination campaigns which took place in the fall of 2009. A small number of Guillain Barré syndrome cases were reported during that period, lower than the number of co-incident background cases.

The immunogenicity of inactivated pandemic H1N1 vaccines was unexpectedly good, as compared to what had been found with prototype H5N1 vaccines. Thus, most inactivated vaccines were able to elicit potentially protective antibody responses in adolescents (9-17 years of age), adults (18-60 years of age) and older adults (>60 years of age) within two weeks of administration of a single dose of vaccine. This was true with split unadjuvanted vaccines containing 15 µg HA per dose, as well as with split vaccines containing 3.75 µg or 7.5 µg HA in the presence of a water-in-oil adjuvant, or with whole-virion vaccines containing either 3.75 µg or 6 µg HA per dose. There was no difference in immunogenicity between egg-derived and cell culture-produced vaccines. Immunogenicity data in children 3-8 years of age showed that with many vaccines, a single dose of vaccine similarly elicited appropriate levels of immune responses, whereas in infants and toddlers aged 6-36 months, a two-dose regimen with a half dose of vaccine was recommended.  A series of studies have been undertaken to attempt to measure H1N1 vaccine effectiveness in the field, although their success may be limited in view of the current loss of intensity of the pandemic.

The participants of the meeting noted that one of the major problems encountered in the development of pandemic H1N1 live attenuated vaccines (LAIVs) was the assessment of their immunogenicity, as broadly applicable immune correlates of protection have not been identified for this type of vaccine. In addition to the development of standardized assays, further research is needed in order to better understand the basis for protection provided by these vaccines, whether virus-specific CD4+ and/or CD8+ T cells, or antibody-based immune mechanisms. The same applies to prototype vaccines using novel technologies. The standardization of already established serological assays (HAI and MN tests) using the new international standard anti-pandemic H1N1 serum will also be necessary in order to optimally compare the relative immunogenicity of different split and whole-virion inactivated vaccines.