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PRIORITY PRESS - 11th Canadian Immunization Conference

Ottawa, Ontario / December 2-4, 2014

Ottawa – The burden of illness associated with influenza infection is considerable, and it is particularly pronounced in the very young and in the elderly. Both groups respond less than optimally to standard influenza vaccines and there is a need to boost immune responses and expand protection against the illness in the most vulnerable age groups. Several immunization strategies can enhance the immunogenicity of any vaccine but one of the more successful strategies is to add a potent adjuvant to the mix. The MF59 adjuvanted trivalent influenza vaccine (MF59-aTIV) has been compared to standard unadjuvanted influenza vaccines in both the very young and in subjects over the age of 65 and was found to produce superior immune responses and to be as safe in both groups. The MF59-aTIV also produces a much more robust antibody response in young children which is important as children need higher antibody levels in order to be protected against influenza. Pregnant women represent another important group who require better protection against influenza than standard vaccines are able to provide and would be an appropriate group to target as well with the MF59-aTIV.

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

The morbidity and mortality from influenza disproportionately affect the very young and the very old. IMPACT data from 12 participating pediatric hospitals across the country indicate that in 2013-2014, approximately 16% of children between 0 and 5 months of age and approximately 28% of children between the ages of 6 and 23 months and 2 to 4 years were hospitalized for influenza. “In terms of hospitalization rates, this is very similar to rates for those aged 65 and older,” Dr. Dat Trans, Professor of Pediatrics, University of Toronto, observed.

The live attenuated influenza vaccine (LAIV) has good efficacy in preventing influenza in children under the age of 6 years, he added, where the number needed to vaccinate to prevent one episode in children between 2 and 6 years of age is only 6. However, there are no data demonstrating efficacy of the LAIV in children ≤2 and inactivated influenza vaccines in children ≤2 are not more effective than placebo in preventing the infection.

Moreover, uptake of the influenza vaccine in young Canadian children is poor, possibly a reflection of a lack of data about the use of the vaccine in the very young and poor efficacy where there is data. At the other end of the age spectrum, the elderly are more likely to succumb to influenza among other respiratory infections because they are prone to develop a fatal secondary bacterial infection.

Immunosenescence is characterized by a number of immune system deficits but the poorer the individual’s functional status, the more likely they are to develop an infection. It therefore becomes increasingly important to try and prevent influenza in the frail elderly in order to prevent what can be a fatal secondary bacterial infection, Dr. Mark Loeb, Division Director, Infectious Diseases, McMaster University, Hamilton emphasized. A Cochrane Review of influenza vaccines  (Cochrane Database Syst Rev. 2010;7:CD001269) showed that depending on the match between the vaccine types and the strains circulating in the community, vaccines afford between 50 to 60% protection against infection in the elderly.

On the other hand, protection rates wane substantially when adjusted for poor functional status, as Dr. Loeb noted.  Faced with significant “immune challenges” in the elderly, strategies to protect this vulnerable population include the use of intradermal and high-dose vaccines, both of which can help stimulate immunogenicity in the setting of immunosenescence.

Research done by Dr. Loeb and colleagues also showed that by vaccinating children in Hutterite colonies, they were able to achieve about a 60% level of protection in those who had never received the vaccine—“suggesting this is an indirect way of protecting adults,” Dr. Loeb said.

The final way to boost immune responses to influenza vaccine is to add an adjuvant to it, he added. 

Adjuvanted Influenza Vaccines

One such adjuvanted influenza vaccine is the MF59 adjuvanted trivalent subunit vaccine (MF59-aTIV) (Fluad^®) which has been used in the elderly in Europe since 1997. “There are no randomized trials evaluating this vaccine,” Dr. Steven Black, Professor of Pediatrics, University of Cincinnati, Cincinnati, Ohio, pointed out. On the other hand, a large-scale observational study, the Lombardia Influenza Vaccine Effectiveness (LIVE) study, was carried out across a number of influenza seasons between 2006 and 2009.

Effectiveness of the MF59-aTIV was compared against a trivalent inactivated vaccine (TIV) in residents 65 years of age and older. It is noteworthy that the adjuvanted vaccine was recommended preferentially for sicker adults in this large observational study. At the end of the study, researchers found that the MF59-aTIV provided 25% greater protection against influenza compared to the TIV during intervals where there was highest influenza activity.

A comparison of the effectiveness of the aTIV and a TIV in community-dwelling and long-term care facility residents found that the aTIV was significantly protective at around 60% in the overall cohort while it was 72% effective among non-long term care residents (Vaccine 2013;31:6122-8).

In children between 6 and 72 months of age, geometric mean titres (GMTs) after two doses of the aTIV reached 746 compared with 92 after two doses of a TIV and 12 for controls who received no influenza vaccine. These GMT levels translated into an 89% efficacy rate for the aTIV compared with 43% for the TIV. Protection against heterologous strains—strains that have “drifted” from strains in the vaccine—is up to six times higher using the adjuvanted vaccine “so not only do you get higher titres against the homologous test strains in the vaccine but you have the potential for protection against these drifted strains with the adjuvanted vaccine as well,” Dr. Black said. Protection was also seen after the first dose of the aTIV which was not seen until after the second dose in the unadjuvanted group, he added.

Higher HI Titres

Importantly, too, hemagglutination inhibition (HI) titres need to be higher in young children than in adults to guarantee protection against influenza infection. In adults, an antibody titre of 1:40 provides approximately 50% protection against infection –“surprisingly more or less what we see from influenza vaccines,” Dr. Black observed. In children, a 50% probability of protection correlates to an antibody titre level of 1:110. To achieve an 80% probability of protection—much closer to levels of protection public health officials would like to see—antibody titre levels have to reach at least 1:330.

In a study by Nolan et al. (Vaccine. 2014;32:6146-56), the MF59-aTIV induced not only faster antibody titres (after a single dose) but higher and more persistent HI titres than comparator non-adjuvanted vaccines and it exhibited consistently higher seroprotection rates at increased threshold HI titres.

The enhanced immunogenicity of the aTIV led to more pronounced HI titres that likely represent more meaningful correlates of clinical protection from influenza in infants and young children, as the authors of the study indicated. Another group in whom a strong argument can be made for the preferential use of the MF59-aTIV is pregnant women.

Recent data indicate that the TIV is only about 50% protective in both pregnant women and in their infants. “Babies born to mothers who develop influenza during pregnancy are at higher risk for prematurity and low birth weight,” Dr. Black said, “so this is another target population where this vaccine might be considered.” No safety issues have emerged for either the adjuvanted or unadjuvanted vaccines given to pregnant women, he added. In young children, reactogenicity of the aTIV is very similar to that of the TIV.

“There has been a lot of experience with this adjuvanted vaccine and all of the evidence points to it being safe in all the populations in which it has been evaluated and the vaccine is more effective in terms of inducing immune responses against both homologous as well as heterologous strains in elderly adults and in children,” Dr. Black concluded.

“[Since] TIV affords less-than-optimal protection in children and the elderly as well as in pregnant women, evidence supports the expanded use of aTIV in these populations.”

Summary

Children under the age of 2 respond poorly to standard injectable influenza vaccines and having a vaccine that is highly effective in infants and young children has the potential to meet a large unmet need in the realm of vaccine-preventable diseases. Similarly, the aging immune system places a large proportion of the population at risk for influenza infection and subsequent complications, while current unadjuvanted vaccines are only modestly effective at protecting pregnant women and their infants from influenza. Compelling arguments can thus be made to expand the use of the aTIV into these 3 populations in particular and reduce the considerable burden of illness associated with the infection.