Theodore Tsai

Estimated global incidence of Japanese encephalitis: a systematic review.

OBJECTIVEnTo update the estimated global incidence of Japanese encephalitis (JE) using recent data for the purpose of guiding prevention and control efforts.nnnMETHODSnThirty-two areas endemic for JE in 24 Asian and Western Pacific countries were sorted into 10 incidence groups on the basis of published data and expert opinion. Population-based surveillance studies using laboratory-confirmed cases were sought for each incidence group by a computerized search of the scientific literature. When no eligible studies existed for a particular incidence group, incidence data were extrapolated from related groups.nnnFINDINGSnA total of 12 eligible studies representing 7 of 10 incidence groups in 24 JE-endemic countries were identified. Approximately 67,900 JE cases typically occur annually (overall incidence: 1.8 per 100,000), of which only about 10% are reported to the World Health Organization. Approximately 33,900 (50%) of these cases occur in China (excluding Taiwan) and approximately 51,000 (75%) occur in children aged 0-14 years (incidence: 5.4 per 100,000). Approximately 55,000 (81%) cases occur in areas with well established or developing JE vaccination programmes, while approximately 12,900 (19%) occur in areas with minimal or no JE vaccination programmes.nnnCONCLUSIONnRecent data allowed us to refine the estimate of the global incidence of JE, which remains substantial despite improvements in vaccination coverage. More and better incidence studies in selected countries, particularly China and India, are needed to further refine these estimates.

MF59 adjuvant: the best insurance against influenza strain diversity

MF59 is a well-established, safe and potent vaccine adjuvant that has been licensed for more than 13 years for use in an influenza vaccine focused on elderly subjects (Fluad®, Novartis, Cambridge, MA, USA). Recently, MF59 was shown to be safe in a seasonal influenza vaccine for young children and was able to increase vaccine efficacy from 43 to 89%. A key and consistent feature of MF59 is the ability of the emulsion to induce fast priming of influenza antigen-specific CD4+ T-cell responses, to induce strong and long-lasting memory T- and B-cell responses and to broaden the immune response beyond the influenza strains actually included in the vaccine. The enhanced breadth of response is valuable in the seasonal setting, but is particularly valuable in a (pre-) pandemic setting, when it is difficult to predict which strain will emerge to cause the pandemic. We have shown that the ability of MF59 to increase the breadth of immune response against influenza vaccines is mainly due to the spreading of the repertoire of the B-cell epitopes recognized on the hemagglutinin and neuraminidase of the influenza virus.

Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy

Abstract Background: A potential association between the new onset of narcolepsy accompanied by cataplexy – a putative autoimmune disorder, and vaccination with an AS03-adjuvanted A(H1N1) pandemic influenza vaccine is under investigation. We sought cases of narcolepsy from the pharmacovigilance database of a pandemic vaccine adjuvanted with another emulsion adjuvant, MF59®, and a pooled clinical trials database of MF59-adjuvanted and non-adjuvanted influenza vaccine recipients. Methods: Using 6 narrowly restrictive and 24 broad sleep disturbance-related MedDRA preferred search terms (PT), we analysed spontaneous adverse events (AEs) reports received through July 31, 2010 and adjudicated suspected cases with onset 1 week–3 months after vaccination, against standardized clinical criteria defining narcolepsy. A pooled clinical trials database of 115 trials comprising 79,004 subjects receiving various MF59-adjuvanted and non-adjuvanted influenza vaccines in controlled and uncontrolled trials was analysed for cases with a narrow PT that had onset 1 week after vaccination. Results: Five thousand three hundred and five spontaneous AE reports were received from an estimated 23.26 million MF59-adjuvanted pandemic vaccine doses that had been administered. No case meeting the clinical definition of narcolepsy was discovered. In the pooled database of controlled clinical trials, no cases were discovered using the narrow PT, and rates and adjusted odds ratio for broad search terms for all temporal windows showed no significant difference between subjects receiving MF59-adjuvanted or non-adjuvanted vaccine. Conclusions: No case of narcolepsy and no evidence of an increased risk of sleep-related AEs were discovered in recipients of MF59-adjuvanted A(H1N1) pandemic and other MF59-adjuvanted influenza vaccine.

Safety and Immunogenicity of a Novel Influenza Subunit Vaccine Produced in Mammalian Cell Culture

BACKGROUNDnImmunization remains the best prevention strategy for influenza, but production constraints for egg-based influenza vaccines have prompted the development of innovative cell culture manufacturing processes. Here, we describe a novel cell culture-derived influenza vaccine (CCIV) produced in Madin-Darby canine kidney cells.nnnMETHODSnThis phase 3, observer-blind, randomized, multicenter study in Poland compared the immunogenicity of a CCIV and a conventional egg-based vaccine. Participants, stratified by age (adults 18-60 years, n = 1300; elderly persons > or = 61 years, n = 1354), received a single intramuscular vaccination. Immunogenicity was assessed 21 days later by hemagglutination inhibition assay. Reactogenicity was assessed using self-completed diary cards.nnnRESULTSnThe immunogenicity of CCIV was noninferior to that of the conventional vaccine for all 3 vaccine strains in both age groups, regardless of underlying health status. Both vaccines fulfilled European Union registration criteria and were well tolerated, with similar incidences of solicited local and systemic reactions in both age groups; the only significant difference was an increased frequency of mild or moderate pain with CCIV than the conventional vaccine among adult (22% vs 17%; P < .05) and elderly (9% vs 5%; P < .001) vaccinees.nnnCONCLUSIONSnCCIV was well tolerated and highly immunogenic in adults 18 years of age or older. Cell culture may offer greater flexibility of supply during periods of high demand for both seasonal and pandemic vaccines.

Current challenges in implementing cell-derived influenza vaccines: implications for production and regulation, July 2007, NIBSC, Potters Bar, UK.

A meeting was held at NIBSC, UK in July 2007 to discuss the implications of progress in the use of cell culture systems for the manufacture of vaccines against influenza. Issues discussed included the effect of using eggs and different cell types in strain selection, development of seed viruses to be used in production and the nature of the reagents to be used in determining vaccine potency. Future studies to progress the field were reviewed.

New technologies for influenza vaccines

Influenza vaccine preparations have been administered to humans since the late 1930s,1 and the diversity of approaches in licensed trivalent seasonal or monovalent pandemic products is unparalleled by vaccines against any other target. These approaches include inactivated whole virus vaccines, detergent or solvent “split” vaccines, subunit vaccines, live attenuated vaccines, adjuvanted vaccines, intramuscular vaccines, intradermal vaccines, intranasal vaccines, egg-produced vaccines and mammalian cell culture-produced vaccines. The challenges of influenza immunization, including multiple co-circulating strains, antigenic change over time, a broad age spectrum of disease, and the threat of pandemics, continue to drive the development of new approaches. This review describes some of the new approaches to influenza immunization that are the subjects of active research and development.

Exposure to MF59-adjuvanted influenza vaccines during pregnancy— A retrospective analysis

Pregnant women are at increased risk for complications and death associated with pandemic H1N1 influenza infection and they are prioritized for vaccination by public health authorities. Few data are available on the safety of adjuvants as components of pandemic vaccines that could be given systematically to pregnant women. Here we review nonclinical and clinical data on pregnancy outcomes associated with exposure to MF59, an adjuvant used in licensed H1N1 pandemic vaccines. Evaluation of the reproductive and developmental toxicity of MF59 alone and of a candidate MF59-adjuvanted H5N1 vaccine in animals demonstrated no evidence of teratogenicity or impact on fetal or early perinatal development. The clinical trial database encompassing all Novartis vaccine studies from 1991 to 2009 was searched to compare pregnancy outcomes in subjects exposed to MF59-adjuvanted or unadjuvanted influenza vaccines. Analysis of the clinical trial database found that the distribution of pregnancy outcomes (normal, abnormal, or ending in induced abortion) was similar in subjects exposed to MF59-adjuvanted and unadjuvanted influenza vaccine at any time in pregnancy and also, specifically, in early pregnancy: the respective proportions reported as a normal pregnancy outcome were 70% and 75%, respectively, overall, and 61% and 68%, respectively, in early pregnancy. Although data from the clinical database are too few to draw definitive conclusions on risks associated with exposure to MF59-adjuvanted influenza vaccines during pregnancy, available observations, so far, indicate no signals of a risk. Further data will be forthcoming from planned post-licensure studies of adjuvanted H1N1 vaccines as they are distributed in the pandemic response.

Fluad®-MF59®-Adjuvanted Influenza Vaccine in Older Adults.

Influenza directly or indirectly contributes to the four leading causes of global mortality, at rates that are highest in older adults. As the proportion of older adults in the Korean population is greater than in most other countries, influenza prevention is a greater public health priority in Korea than elsewhere. Conventional inactivated influenza vaccine (IIV) is less immunogenic and efficacious (-50%) in older than in young adults, but adjuvanting the vaccine with oil-in-water emulsion MF59® increases immunogenicity, resulting in comparatively higher levels of hemagglutination inhibition antibodies and greater protection against all influenza, as well as cases requiring hospitalization. A recent observational study demonstrated that the adjuvanted vaccine protected older adults against influenza in a year when nonadjuvanted IIV was ineffective. In another multiyear study, the adjuvanted vaccine was estimated to be 25% more effective in preventing pneumonia and influenza hospitalizations compared to nonadjuvanted vaccine. Although MF59-adjuvanted vaccine is transiently more reactogenic than nonadjuvanted vaccine, there is no evidence that it increases risks for serious adverse events, including those with an autoimmune etiology. Experience thus far indicates a favorable balance of benefit to risk for MF59. This may reflect the adjuvants mechanism of action in which the squalene oil emulsion increases antibody responses to co-administered antigen without acting more generally as an immunopotentiator.

Viscerotropic disease: Case definition and guidelines for collection, analysis, and presentation of immunization safety data

iscerotropic disease: Case definition and guidelines for collection, analysis, and resentation of immunization safety data ark D. Gershmana,∗, J. Erin Staplesb, Adwoa D. Bentsi-Enchill c, J. Gabrielle Breugelmansd, lacus S. Britoe, Luiz Antonio Bastos Camachof, Pascale Cotting, Cristina Domingoh, Anna Durbin i, oaquim Gasconj, Fouzia Guenanechek,1, Edward B. Hayes j, Zsuzsanna Jelenik l, Alena Khromavam, einaldo de Menezes Martinsn, Mario Masana Wilsono,2, Nathalie Massyp, Abdulsalami Nasidiq, atthias Niedrigh, Adam Sherwatr,3, Theodore Tsai s, Anna Vilella j, Mary Elizabeth Wilsont, atrin S. Kohla , The Brighton Collaboration Viscerotropic Disease Working Group

Emulsion-Based Adjuvants for Improved Influenza Vaccines

Emulsions have a long history of use as potent and effective adjuvants in humans for a range of vaccines, particularly for influenza. Although older mineral oil- and water-in-oil-based emulsion adjuvants did not have an overall safety and tolerability profile to allow them to be acceptable for widespread use, a newer generation of oil-in-water adjuvants has been recently developed, based on the use of the biodegradable oil squalene. These adjuvants have shown particular value in the development of new generation vaccines to offer enhanced protection against both seasonal and pandemic strains of influenza virus. The first oil-in-water emulsion adjuvant included in an approved flu vaccine was MF59, which was originally licensed in Europe in 1997 as an improved influenza vaccine for the elderly. In the very recent past, MF59 and related adjuvants have shown their value by offering the possibility of significant antigen dose reductions and higher potency products in the face of the H1N1 pandemic emergency and other pandemic threats. The recent H1N1 global problem allowed the opportunity for widespread use of emulsion-based adjuvants in a range of population groups in a number of countries, in which strict monitoring of safety was the norm. Importantly, this widespread use allowed the safety profile of squalene-based emulsion adjuvants to be further substantiated in large and diverse populations of humans, including young children and pregnant women. It is our confident prediction that the coming years will see wider use and further licensures for oil-in-water emulsion adjuvants, particularly for improved flu vaccines.