Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial

Influenza is a major cause of worldwide morbidity and mortality through frequent seasonal epidemics and infrequent pandemics. Morbidity and mortality rates from seasonal influenza are highest in the most frail, such as the elderly, those with underlying chronic conditions and very young children. Antigenic mismatch between strains recommended for vaccine formulation and circulating viruses can further reduce vaccine efficacy in these populations. Seasonal influenza vaccines with enhanced, cross‐reactive immunogenicity are needed to address these problems and can confer a better immune protection, particularly in seasons were antigenic mismatch occurs. A related issue for vaccine development is the growing threat of pandemic influenza caused by H5N1 avian strains. Vaccines against strains with pandemic potential offer the best approach for reducing the potential impact of a pandemic. However, current non‐adjuvanted pre‐pandemic vaccines offer suboptimal immunogenicity against H5N1. For both seasonal and pre‐pandemic vaccines, the addition of adjuvants may be the best approach for providing enhanced cross‐reactive immunogenicity. MF59®, the first oil‐in‐water emulsion licensed as an adjuvant for human use, can enhance vaccine immune responses through multiple mechanisms. A trivalent MF59‐adjuvanted seasonal influenza vaccine (Fluad®) has shown to induce significantly higher immune responses to influenza vaccination in the elderly, compared with non‐adjuvanted vaccines, and to provide cross‐reactive immunity against divergent influenza strains. Similar results have been generated with a MF59‐adjuvanted H5N1 pre‐pandemic vaccine, which showed higher and broader immunogenicity compared with non‐adjuvanted pre‐pandemic vaccines.

Section: Introductionmentioning

confidence: 99%

MF59^®‐adjuvanted vaccines for seasonal and pandemic influenza prophylaxis

Banzhoff

Pellegrini

Giudice

et al. 2008

“…Haemagglutination‐inhibition geometric mean titres (GMTs) of 13·9–57·4 and MN GMTs of 15·7–45·1 were developed in the four groups 14 days after the second dose. The highest immune response of 78% HI seroconversion and seroprotection rates and a 11·5 post‐to‐pre‐vaccination GMT ratio was elicited after two doses of 10 μg vaccine, meeting all three EU CHMP licensure criteria for HI GMT ratio (>2·5), seroconversion rate (>40%) and seroprotection rate (>70%) 4 , 6 …”

Section: Immunogenicitymentioning

confidence: 99%

“…The whole‐virion H5N1 vaccine was firstly evaluated in adults in a phase I trial enrolling 120 participants with 24 of them receiving placebo 6 . The results showed that the four vaccine doses (1·25, 2·5, 5 and 10 μg) were well tolerated with no serious adverse events reported.…”

Section: Safetymentioning

confidence: 99%

“…Many promising H5N1 vaccines including whole‐virion, split‐virion, adjuvanted and non‐adjuvanted vaccines have been developed and clinically evaluated, 6 , 11 , 12 , 13 some of which have been granted production licensure in different regions. All these achievements arm us with a powerful, if not sufficient, defence against the next human influenza pandemic.…”

Section: Problem and Prospectmentioning

confidence: 99%

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Safety and immunogenicity of Sinovac’s prototype pandemic influenza H5N1 vaccines: a review on clinical trials

Qiu

Yin

2008

Sinovac Biotech started to develop prototype pandemic influenza H5N1 vaccines in March 2004. On 2 April 2008, Sinovac’s inactivated, aluminium‐adjuvanted, whole‐virion prototype pandemic influenza A (H5N1) vaccine (PanFlu™) was granted production licensure by the China regulatory authority State Food and Drug Administration. The whole‐virion H5N1 vaccine was manufactured in embryonated hens’ eggs using the reassortant strain NIBRG‐14 (A/Vietnam/1194/2004‐A/PR/8/34) as vaccine virus. It showed good safety, immunogenicity and cross‐reactivity in immunologically naïve adults. In primed adults, the vaccine induced a strong booster response. Plasma from a vaccinated individual showed a beneficial effect following passive immunotherapy of an H5N1 human infection case. This article reviews the process, status and results of clinical evaluation of Sinovac’s whole‐ and split‐virion H5N1 vaccines by focusing on the whole‐virion vaccine.

“…Although virus transmission from person to person is as yet minimal, 2 human viral infections have the potential of developing into the source of the next influenza pandemic, therefore the development of effective vaccines against the influenza A (H5N1) virus is a matter of considerable urgency. Previous work suggests that, in naïve humans, whole‐virion vaccine formulations are more immunogenic than subunit formulations and the use of adjuvants improves immunogenicity 3 , 4 , 5 , 6 , 7 , 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

Characterization of a whole, inactivated influenza (H5N1) vaccine

Tada

2008

Objectives Effective vaccines against the highly pathogenic influenza A/H5N1 virus are being developed worldwide. In Japan, two adjuvanted, inactivated, whole‐virion influenza vaccines were recently developed and licensed as mock‐up, pre‐pandemic vaccine formulations by the Ministry of Health and Labor Welfare of Japan. During the vaccine design and development process, various obstacles were overcome and, in this report, we introduce the non clinical production, immunogenicity data in human and development process that was associated with egg‐derived adjuvanted, inactivated, whole‐virion influenza A (H5N1) vaccine. Design Pilot lots of H5N1 vaccine were produced using the avirulent H5N1 reference strain A/Vietnam/1194/2004 (H5N1) NIBRG‐14 and administered following adsorption with aluminum hydroxide as an adjuvant. Quality control and formulation stability tests were performed before clinical trials were initiated (phase I‐III). The research foundation for microbial diseases of Osaka University (BIKEN) carried out vaccine production, quality control, stability testing and the phase I clinical trial in addition to overseeing the licensing of this vaccine. Mitsubishi Chemical Safety Institute Ltd. carried out the non clinical pharmacological toxicity and safety studies and the Japanese medical association carried out the phase II/III trials. Phase I‐III trials took place in 2006. Results The production processes were well controlled by established tests and validations. Vaccine quality was confirmed by quality control, stability and pre‐clinical tests, and the vaccine was approved as a mock‐up, pre‐pandemic vaccine by the Ministry of Health and Labor Welfare of Japan. Conclusions Numerous safety and efficacy procedures were carried out prior to the approval of the described vaccine formulation. Some of these procedures were of particular importance e.g., vaccine development, validation, and quality control tests that included strict monitoring of the hemagglutinin (HA) content of the vaccine formulations. Improving vaccine productivity, shortening the production period and improving antigen yield of the avirulent vaccine strains were also considered important vaccine development criteria.