Advanced Age and Increased Risk for Severe Outcomes of Dengue Infection, Taiwan, 2014-2015.

Dengue, a mosquitoborne flavivirus infection, is increasingly a disease of older adults who are more likely to have chronic diseases that confer risk for severe outcomes of dengue infection. In a population-based study in Taiwan, adjusted risks for dengue-related hospitalization, intensive care unit admission, and death increased progressively with age.

Oil-in-water emulsion adjuvant with influenza vaccine in young children.

BACKGROUND: The efficacy of inactivated influenza vaccines is known to be poor in infants and young children. METHODS: We studied the effect of the adjuvant MF59, an oil-in-water emulsion, on the efficacy of trivalent inactivated influenza vaccine (TIV) in 4707 healthy children 6 to less than 72 months of age who had not previously been vaccinated against influenza. The children were randomly assigned to three study groups, each of which received the assigned vaccines in two doses, 28 days apart, during two consecutive influenza seasons. Two of the groups were given age-appropriate doses of TIV either with or without the MF59 adjuvant, and the third group was given control (noninfluenza) vaccines to assess their absolute and relative efficacy against influenza-like illness, as confirmed by means of polymerase-chain-reaction (PCR) assay. RESULTS: Attack rates of influenza-like illness across both influenza seasons were 0.7%, 2.8%, and 4.7% in the adjuvant, nonadjuvant, and control vaccine groups, respectively. The absolute vaccine efficacy rates against all influenza strains (94 of 110 cases were due to vaccine-matched H3N2 viruses) were 86% (95% confidence interval [CI], 74 to 93) for the MF59-adjuvant vaccine (ATIV) and 43% (95% CI, 15 to 61) for the vaccine without the adjuvant (TIV); the relative vaccine efficacy rate for ATIV versus TIV was 75% (95% CI, 55 to 87). The efficacy rates for ATIV were 79% (95% CI, 55 to 90) in children 6 to less than 36 months of age and 92% (95% CI, 77 to 97) in those 36 to less than 72 months of age, as compared with 40% (95% CI, -6 to 66) and 45% (95% CI, 6 to 68), respectively, for TIV. Antibody responses were higher with ATIV and remained so through day 181. The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group (relative risk, 1.04; 95% CI, 0.98 to 1.09), but systemic events in the older age group were more frequent after administration of ATIV (63%) than after administration of TIV (44%) or the control vaccine (50%). Serious adverse events were distributed evenly across the three vaccine groups. CONCLUSIONS: Influenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children. (Funded by Novartis Vaccines and Diagnostics; ClinicalTrials.gov number, NCT00644059.).

Estimated global incidence of Japanese encephalitis: a systematic review.

OBJECTIVE: To update the estimated global incidence of Japanese encephalitis (JE) using recent data for the purpose of guiding prevention and control efforts. METHODS: Thirty-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. FINDINGS: A 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. CONCLUSION: Recent 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.

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

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.

Cell culture-derived influenza vaccines in the severe 2017-2018 epidemic season: a step towards improved influenza vaccine effectiveness.

The 2017-2018 seasonal influenza epidemics were severe in the US and Australia where the A(H3N2) subtype viruses predominated. Although circulating A(H3N2) viruses did not differ antigenically from that recommended by the WHO for vaccine production, overall interim vaccine effectiveness estimates were below historic averages (33%) for A(H3N2) viruses. The majority (US) or all (Australian) vaccine doses contained multiple amino-acid changes in the hemagglutinin protein, resulting from the necessary adaptation of the virus to embryonated hen's eggs used for most vaccine manufacturing. Previous reports have suggested a potential negative impact of egg-driven substitutions on vaccine performance. With BARDA support, two vaccines licensed in the US are produced in cell culture: recombinant influenza vaccine (RIV, Flublok™) manufactured in insect cells and inactivated mammalian cell-grown vaccine (ccIIV, Flucelvax™). Quadrivalent ccIIV (ccIIV4) vaccine for the 2017-2018 influenza season was produced using an A(H3N2) seed virus propagated exclusively in cell culture and therefore lacking egg adaptative changes. Sufficient ccIIV doses were distributed (but not RIV doses) to enable preliminary estimates of its higher effectiveness relative to the traditional egg-based vaccines, with study details pending. The increased availability of comparative product-specific vaccine effectiveness estimates for cell-based and egg-based vaccines may provide critical clues to inform vaccine product improvements moving forward.

Invasive pneumococcal disease burden in Hong Kong children.

In a retrospective, population-based study, we estimated the age-specific incidence of invasive pneumococcal disease in Hong Kong between 1995 and 2004. The incidence rates per 100,000 were 18.3 (95% confidence interval [CI], 13.9-23.3) for children aged

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 adjuvant's mechanism of action in which the squalene oil emulsion increases antibody responses to co-administered antigen without acting more generally as an immunopotentiator.

Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial.

BACKGROUND: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response. METHODS: The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively. RESULTS: 58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29). CONCLUSION: Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557.

New technologies for influenza vaccines.

Influenza vaccine preparations have been administered to humans since the late 1930s, 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.

MF59 adjuvanted seasonal and pandemic influenza vaccines.

MF59-adjuvanted seasonal trivalent inactivated (ATIV) vaccine licensed since 1997 and MF59-adjuvanted pandemic H1N1 vaccines have been distributed to approximately 80M persons. Addition of the emulsion adjuvant to inactivated vaccine formulations provides for higher levels of antibody to the viral hemagglutinin (HA) in less responsive older adults, infants and children which, in the case of the pandemic vaccine, allowed only 3.75 µg of the HA to be immunogenic. The adjuvant also stimulates production of more broadly-reactive antibodies against strains that are mismatched to those in the vaccine, a potential advantage in the face of perennial influenza virus antigenic drift. In a field trial, ATIV was 89% efficacious in preventing laboratory-confirmed influenza in 6-<72 month old children, 81% more efficacious than the unadjuvanted control split vaccine while, in older adults, ATIV reduced community-acquired pneumonia and influenza hospitalizations in adults >65 years old by 23% compared to unadjuvanted vaccine, in an observational study. The effectiveness of MF59 adjuvanted split pandemic H1N1 vaccine was 74% overall. Unadjuvanted pandemic vaccine was poorly immunogenic in HIV-infected persons, whereas their responses to MF59-adjuvanted vaccine were similar to those of healthy controls. Analyses of the clinical trials and pharmacovigilance databases and observational studies have shown that while MF59-adjuvanted influenza vaccines are more locally reactogenic, they have not been associated with an increased risk for various adverse effects (AE) of special interest, including unsolicited neurological or autoimmune events.

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.

Early appearance of bactericidal antibodies after polysaccharide challenge of toddlers primed with a group C meningococcal conjugate vaccine: what is its role in the maintenance of protection?

The contribution of memory responses after meningococcal vaccination to protection may depend on the rapidity of the response. Toddlers were challenged with a licensed polysaccharide (PS) vaccine 1 year after vaccination with a single dose of meningococcal group C-CRM(197) conjugate (MCC) vaccine at the age of 12 to 15 months. Bactericidal antibodies and immunoglobulin G (IgG) antibodies detected by an enzyme-linked immunosorbent assay (ELISA) were measured before challenge and 4, 7, 14, or 21 Days later ("Days" refer to treatment groups, "days" to sampling days). Among 281 subjects in the intent-to-treat population, 173 per-protocol (PP) subjects were challenged with 10 microg PS antigen and 103 others with a 50-microg PS vaccinating dose. Capsular PS-specific ELISA IgG titers were negligible in baseline samples and increased only twofold within 4 days of PS administration. In contrast, the proportion of PP subjects with serum bactericidal antibody (SBA) titers of >or=1:8 or >or=1:128 increased, respectively, from 41% and 16% before challenge to 84% and 74% at Day 4 and to 100% and 97% at Day 7. Recipients of 50 microg PS responded with similar kinetics but showed a trend toward higher antibody levels. Unexpectedly, 69% of subjects bled on days 2 to 3 already had achieved SBA titers of >or=1:8. The majority of toddlers previously immunized with MCC and challenged 1 year later with PS antigen mounted protective levels of bactericidal antibody within 2 to 4 days.

Advanced age a risk factor for illness temporally associated with yellow fever vaccination.

In 1998, the Centers for Disease Control and Prevention was notified of severe illnesses and one death, temporally associated with yellow fever (YF) vaccination, in two elderly U.S. residents. Because the cases were unusual and adverse events following YF vaccination had not been studied, we estimated age-related reporting rates for systemic illness following YF vaccination. We found that the rate of reported adverse events among elderly vaccinees was higher than among vaccinees 25 to 44 years of age. We also found two additional deaths among elderly YF vaccinees. These data signal a potential problem but are not sufficient to reliably estimate incidence rates or to understand potential underlying mechanisms; therefore, enhanced surveillance is needed. YF remains an important cause of severe illness and death, and travel to disease-endemic regions is increasing. For elderly travelers, the risk for severe illness and death due to YF infection should be balanced against the risk for systemic illness due to YF vaccine.

Evaluation of combined live, attenuated respiratory syncytial virus and parainfluenza 3 virus vaccines in infants and young children.

We evaluated a combination respiratory syncytial virus (RSV) and parainfluenza 3 virus (PIV3) live, attenuated intranasal vaccine for safety, viral replication, and immunogenicity in doubly seronegative children 6-18 months old. RSV cpts-248/404 and PIV3-cp45 vaccines were combined in a dose of 10(5) plaque-forming units of each per 0.5-mL dose and compared with monovalent vaccines or placebo. The virus shedding pattern of RSV was not different between monovalent RSV cpts-248/404 vaccine and combination vaccine. Modest reductions in the shedding of PIV3-cp45 vaccine virus were found after the administration of RSV cpts-248/404 and PIV3-cp45 vaccine, relative to monovalent PIV3 vaccine; 16 (76%) of 21 children given combination vaccine shed PIV3-cp45 versus 11 (92%) of 12 of those given monovalent PIV3 vaccine. Both vaccines were immunogenic, and antibody responses were similar between the monovalent groups and the combination group. Combined RSV/PV3 vaccine is feasible for simultaneous administration, and further studies are warranted.

Phase 2 evaluation of parainfluenza type 3 cold passage mutant 45 live attenuated vaccine in healthy children 6-18 months old.

A phase 2 evaluation of live attenuated parainfluenza type 3 (PIV3)-cold passage mutant 45 (cp45) vaccine was conducted in 380 children 6-18 months old; 226 children (59%) were seronegative for PIV3. Of the 226 seronegative children, 114 received PIV3-cp45 vaccine, and 112 received placebo. No significant difference in the occurrence of adverse events (i.e., runny nose, cough, or temperature > or =38 degrees C) was noted during the 14 days after vaccination. There was no difference between groups in the occurrence of acute otitis media or serous otitis media. Paired serum samples were available for 109 of the seronegative vaccine recipients and for 110 of the seronegative placebo recipients; 84% of seronegative vaccine recipients developed a > or =4-fold increase in antibody titers. The geometric mean antibody titer after vaccination was 1 : 25 in the vaccine group and <1 : 4 in the placebo group. PIV3-cp45 vaccine was safe and immunogenic in seronegative children and should be evaluated for efficacy in a phase 3 field trial.