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Novel Adjuvant in Trivalent Inactivated Influenza Vaccine for Very Young Children

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDI-NEWS Based on Vesikari et al. N Engl J Med 2011;365:1406-16.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

An adjuvanted trivalent inactivated influenza vaccine (ATIV) has proven highly protective against influenza illness in very young children, according to a large-scale, phase III clinical trial. The same ATIV has additional potential advantages over the non-adjuvanted TIV of increased heterovariant coverage, longer duration of protection and, for some influenza strains, protection after a single dose.

Dr. Timo Vesikari, University of Tampere Medical School, Finland, and multicentre colleagues assessed the effect of adding the MF59 oil-in-water emulsion on the efficacy of TIV in 4707 healthy children 6 to <72 months of age not previously vaccinated against influenza. Children were randomly assigned to 1 of 3 study groups: 2 were given age-appropriate doses of TIV either with or without the MF59 adjuvant; the third group was given a control vaccine. Each group received 2 doses of the assigned vaccine, 28 days apart, during 2 consecutive influenza seasons.

The study was conducted across the 2007-2008 influenza season in Germany and during the 2008-2009 influenza season in Germany and Finland. “Participants were stratified according to age (6 to <36 months and 36 to <72 months),” investigators noted, “and the principal study objectives were to show that in children 6 to less than 36 months of age, ATIV has an acceptable level of combined local and systemic reactogenicity as compared with TIV and superior protective efficacy as compared with control vaccine, against vaccine-matched influenza illness confirmed by means of real-time polymerase-chain-reaction (PCR) assessment.”

As investigators reported, attack rates of influenza-like illness across both influenza seasons were 0.7% for the ATIV group, 2.8% for the nonadjuvant TIV group and 4.7% for the control vaccine groups. (Vaccine efficacy was not calculated for year 1 as there were only 5 cases of influenza.)

The absolute efficacy of ATIV across both influenza seasons was 86% against all strains vs. 43% for the TIV. Against vaccine-matched strains and the H3N2 virus, the ATIV was more effective at 89% vs. 45% for the TIV. The ATIV was also effective in both age groups.

In children 6 to <36 months of age, vaccine efficacy was 79% against all strains, while in children 36 to <72 months, vaccine efficacy was 92% against all strains. Specific efficacy rates for the TIV comparator were not reported for each age subgroup but point estimates in each subgroup were similar. The relative efficacy rates for the ATIV according to age group were 64% against all strains and 68% against matched strains among children who were 6 to <36 months and 86% and 91%, respectively, among children 36 to <72 months.

On the basis of these results, the ATIV had a higher relative efficacy than TIV in the entire cohort at 75% against all strains and 80% against vaccine-matched strains and the H3N2 virus. The highest relative efficacy rates were seen in the older age cohort against all and vaccine-matched strains.

Noteworthy Findings

The authors also noted that a post hoc analysis in children 6 to <24 months of age showed that the overall efficacy of the ATIV against matched strains was 75% compared to almost no efficacy for the TIV at 2%. The latter observation is “noteworthy” as the authors pointed out, because efficacy of the TIV in children <24 months is very limited.

Investigators also assessed the proportion of children with seroprotective hemagglutination-inhibition antibody titres (=40) against homologous (vaccine) influenza A H1N1 and H3N2 strains after 1 and 2 doses of both trivalent inactivated vaccines. In the younger age cohort, over 90% achieved seroprotective titres against both influenza strains after 1 dose of the ATIV compared with between 12% and 20% of those vaccinated with 1 dose of the TIV. Among the older age cohort, the respective proportions who achieved seroprotective titres against the same 2 strains were 100% and 97% for ATIV recipients vs. 63% vs. 60% for TIV recipients. “Moreover, 98 to 100% of all ATIV recipients still had seroprotective titres against these strains at day 181, whereas the respective proportions for TIV recipients were 49% and 65%,” investigators added.

As for the homologous influenza B strain, researchers noted that 2 doses of the ATIV elicited seroprotective antibody titres in 88% of the younger children and in 99% of the older children. With respect to the TIV vaccine seroprotective antibody titres were 19% for younger children and 60% for older children. As the authors noted, seroprotective antibody titres after 2 doses of the ATIV declined significantly in both age cohorts by day 181 but they declined dramatically more following 2 doses of the TIV.

Low responses to the B strain in children are of particular concern, investigators noted, since this age group has a disproportionate share of influenza B virus infections. Moreover, “B strains are frequently responsible for late-season (spring) influenza outbreaks, so the high proportion of children with seroprotective hemagglutination-inhibition antibody titres at day 181 (64%) and the maintenance of vaccine efficacy through the end of the influenza season are potential advantages of ATIV over TIV, particularly with the start of vaccine deliveries and immunizations in August,” they added.

As investigators noted, the relative risk of solicited adverse events (AEs) after 1 or 2 doses of ATIV was 1.04 compared with TIV, “fulfilling the primary safety hypothesis.” Local AEs were reported more frequently for both ATIV recipients (54%) and for controls (52%) than for TIV recipients (46%) but systemic AE rates were similar across all 3 groups. Among children who were 36 to less than 72 months of age, local AEs were reported in 68%, 60% and 55% of recipients of ATIV, TIV and control vaccines, respectively, whereas systemic AEs were more frequent among ATIV recipients (63%) and control vaccine recipients (50%) than among TIV recipients (44%). That said, the majority of both local and systemic AEs, including fever, were mild or moderate and transient, as investigators observed.

Questions and Answers

Question and Answers with Dr. David W. Scheifele, Vaccine Evaluation Center, Child and Family Research Institute, Vancouver, and Professor of Pediatrics, University of British Columbia.

Q: Currently, standard influenza vaccines are recommended for children from 6 months of age onwards, with some provinces supplying them for the 6- to 24-month age group. But how well do they work and how much better would adjuvanted vaccines be?

A: As the paper showed, the currently available standard vaccine does not work nearly as well in young children as one would like. In adulthood, we have all had many influenza infections and together with vaccination, that helps us build considerable immunity against influenza so as adults, we are simply boosting immunity from year to year and tailoring it a bit towards changes in the virus. Young children are encountering influenza for the first time, and the standard vaccine is not potent enough to bring about good protection with a single vaccination sequence. So children need a boost and adjuvanted vaccine is the additional boost that would help this young age group respond more effectively to the vaccine. It is very much a direction we would like to see immunization programs move.

Q: Could you comment on the AE profile of the ATIV?

A: Children tolerate the standard influenza vaccine very well; in fact, they have fewer side effects than adults. This paper showed that there was very little difference between the standard and adjuvanted TIV, perhaps a little more injection-site reactions with the adjuvanted vaccine but apart from that, it looked pretty good.

Q: We know the influenza vaccination rate is quite low in children. If we had a more effective vaccine for young children, do you think that might increase the vaccination rate?

A: Of course. The trivalent inactivated vaccine is the least effective vaccine that we use with any regularity in children; the other childhood vaccines have efficacy rates in the 90% range and here we are talking about a vaccine with only about a 40% efficacy rate and you have to do it every year.

Q: How important an advance is this adjuvanted vaccine compared with current vaccines for young children?

A: Potentially it is a huge advance….[if it] makes it to the market—and I’m reasonably confident it will—it will make a huge difference to how the annual influenza epidemic unfolds. A highly effective vaccine that is well subscribed to by the public will protect not only children more effectively, but it will [also] curtail illness in families and beyond into the workplace. So this could have ramifications across the whole age range just by doing a better job at controlling influenza in young children.

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