Immunogenicity of aIIV3, MF59-adjuvanted seasonal trivalent influenza vaccine, in older adults ≥65 years of age: Meta-analysis of cumulative clinical experience.

OBJECTIVE: Compare the immunogenicity of MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3; Fluad™) versus conventional trivalent inactivated influenza vaccine (IIV3) in an integrated dataset using a meta-analysis. METHODS: In a meta-analysis, the immunogenicity of aIIV3 in subjects ≥65 years of age was compared with IIV3 immunogenicity using hemagglutination inhibition assay results from 23 phase I through III randomized controlled trials, including 16 first-dose vaccination studies and 7 revaccination studies assessing immunogenicity after second or third annual vaccination. RESULTS: The full analysis set consisted of 11,105 subjects (5869 aIIV3 and 5236 IIV3). In the revaccination studies, 822 individuals received 2 consecutive annual influenza vaccinations (492 aIIV3 and 330 IIV3), and 237 received 3 (150 aIIV3 and 87 IIV3). Overall, across all strains, the meta-analyzed point estimates for seroconversion (SC) and geometric mean titer (GMT) ratio were significantly higher for aIIV3 versus IIV3. The meta-analyzed percent differences in SC with corresponding 95% confidence intervals (CI) for A/H1N1, A/H3N2, and B strain were 9.5% (5.2-13.9), 10.5% (6.6-14.5), and 12.7% (8.6-16.8), respectively. The meta-analyzed GMT ratios with corresponding 95% CI for A/H1N1, A/H3N2, and B strain were 1.15 (1.01-1.31), 1.30 (1.18-1.44), 1.23 (1.15-1.31). Antibody responses against heterologous influenza strains were also significantly higher with aIIV3. Revaccination studies showed continued robust immune response to aIIV3 with repeated vaccination. CONCLUSIONS: aIIV3 elicited a statistically significantly greater immune response compared to conventional IIV3 in older adults, increasing the breadth and duration of the immune response.

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.

Safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents: an integrated analysis.

We reviewed the safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents (aged 6 months-18 years) in an integrated analysis of all pediatric trials evaluating MF59-containing influenza vaccines completed to date (5 trials). In the MF59-adjuvanted group (n=1181) versus the non-adjuvanted group (n=545) there was no increase in the incidence of unsolicited adverse events and serious adverse events. As expected, solicited local or systemic reactions occurred more frequently in MF59-adjuvanted subjects; however, a majority of reactions were mild and transient. These data support the safety of MF59-adjuvanted influenza vaccines in the pediatric population.

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.

Double-blind study comparing the immunogenicity of a licensed DTwPHib-CRM197 conjugate vaccine (Quattvaxem) with three investigational, liquid formulations using lower doses of Hib-CRM197 conjugate.

We performed a double-blind clinical study to evaluate the safety and immunogenicity of four formulations of a DTwPHib full liquid vaccine, three of which contained fractional doses of the 10 microg-dose of CRM197-Hib conjugate vaccine. A total of 261 infants were enrolled and randomised to receive at 3, 4 and 5 months of age, in a double-blind fashion, one of the four DTwPHib vaccine formulations containing 10, 5, 2.5 or 1.25 microg of CRM197-Hib conjugate. Post-immunization reactions were similar in the four vaccine groups, they were mild, transient and resolved without sequelae. The seroconversion rates to anti-PRP titres > or = 0.15 microg/mL were 100%, 98%, 97% and 98% in the groups 10, 5, 2.5 and 1.25 microg, respectively. The seroconversion rates to anti-PRP titres > or =1 microg/mL were 95%, 97%, 88% and 90%, again respectively. Anti-PRP GMTs were 18, 17, 7.82 and 6.94 microg/mL, respectively. All subjects were protected against tetanus and diphtheria, and >80% seroconverted to pertussis. High, and similar, levels of anti-PRP GMTs were elicited by the formulations with 10 and 5 microg of CRM197-Hib conjugate. Although the formulations with 2.5 and 1.25 microg of CRM197-Hib elicited lower levels of anti-PRP GMTs, they were immunogenic and are possible candidates for further development.

Safety and immunogenicity of two Haemophilus influenzae type b conjugate vaccines.

OBJECTIVES: Haemophilus influenzae type b (Hib) infection remains a major public health problem in the developing world. We evaluated the safety and immunogenicity of a new PRP-CRM197 conjugate Hib vaccine (Vaxem Hib, Chiron Vaccines), compared with the HibTITER vaccine (Wyeth-Lederle Vaccines), following the World Health Organisation (WHO)'s accelerated schedule which allows 4-week intervals between doses. STUDY DESIGN: A phase II, observer-blind, multicentre, randomised, controlled, non-inferiority study. METHODS: In total, 331 babies were immunised with either Vaxem Hib (N = 167) or HibTITER (N = 164) vaccine at 6, 10 and 14 weeks of age, in parallel with oral polio, diphtheriatetanus-pertussis and hepatitis B vaccines. Post-immunisation reactions were recorded after each immunisation and at follow-up visits. Anti-polyribosylribitol phosphate (PRP) antibodies were measured using enzyme-linked immunosorbent assays (ELISAs) before and 1 month after the third immunisation. RESULTS: Overall, there was no significant difference in the anti-PRP levels between the two groups. One month after the third immunisation, 76% of vaccinees in the Vaxem Hib group and 70% in the HibTITER group had anti-PRP antibody titres > or = 1.0 microgram/ml, while 96% of the Vaxem Hib group and 90% of the HibTITER group demonstrated anti-PRP antibody titres > or = 0.15 microgram/ml. The geometric mean titre at day 90 was 3.77 micrograms/ml for the Vaxem Hib and 3.0 micrograms/ml for the HibTITER groups. Although the Vaxem Hib vaccine produced more redness (6% versus 1%; p = 0.006) and swelling (5% versus 1%, p = 0.037), overall it was well tolerated compared with the HibTITER vaccine. There was no significant difference in vaccine-related elevated temperature (> or = 38 degrees C) between the two groups (p = 0.11). CONCLUSION: Both vaccines showed comparable safety and immunogenicity profiles when administered to South African babies at 6, 10 and 14 weeks of age.

A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis.

BACKGROUND: The elderly are at a higher risk of morbidity and mortality associated with influenza infection than younger adults, but get less protection from conventional vaccination. OBJECTIVE: We conducted a meta-analysis of all available data from clinical trials in the elderly on a recently introduced MF59-adjuvanted influenza vaccine to determine its immunogenicity and safety in subjects with underlying chronic disease who are at highest risk of influenza infection. METHODS: Data on immunogenicity and safety from 3600 subjects immunized with either the MF59-adjuvanted or conventional comparator influenza vaccine in 13 clinical trials were analyzed by disease history. Geometric mean haemagglutination inhibition titres (GMTs) and differences between the vaccine groups were compared using two-way analysis of variance. Differences between vaccine groups in the percentages with post-immunization reactions were assessed using chi-squared test and Fischer's exact test. RESULTS: At 28 days the adjuvanted:comparator GMT ratio for the A/H3N2 antigen was 1.18 in healthy elderly subjects and 1.43 in elderly subjects with chronic disease (p = 0.004). The respective GMT ratios were 1.17 versus 1.37 for the B antigen (p = 0.065) and 1.10 versus 1.17 for the A/H1N1 antigen (p = 0.41). Although post-immunization reactions were more common in the group receiving the adjuvanted vaccine, these were predominantly mild and transient, and none were serious. CONCLUSIONS: The MF59-adjuvanted influenza vaccine is more immunogenic in elderly subjects than conventional non-adjuvanted influenza vaccines and especially so in those with chronic disease. Therefore, since its safety profile is clinically acceptable, this adjuvanted vaccine represents an excellent option for influenza immunization of elderly subjects at highest risk of complications.