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The Wide World of Vaccines

December 2019

Tricky Influenza Vaccine Dosing and Two Experimental Strategies to Improve Responses in Children <9 Years Old 
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Christopher J. Harrison, MD, FAAP, FPIDS
 | Director, Vaccine and Treatment Evaluation Unit | Professor of Pediatrics, UMKC School of Medicine

Children respond insufficiently when the first dose of inactivated influenza virus vaccine (IIV) or live-attenuated influenza vaccine (LAIV) is given prior to 9 years of age. Vaccine effectiveness and immune responses appear to be even less robust when children are less than 3 years of age.

For decades, children receiving their first doses before 9 years old were considered “fully vaccinated” only if they got two doses (“priming” dose followed >4 weeks later by “booster” dose) of the same seasonal vaccine in the same season. If children got only one dose in their first immunized season, they were considered incompletely vaccinated. So the following season, they still needed two doses (priming, plus booster) to be considered fully vaccinated for that new season. But after a priming and booster in any season, only one dose would be needed in subsequent seasons. Several years ago, recommendations changed to allow any dose of seasonal IIV or LAIV at any time prior to the current season to act as the priming dose, so only one dose in the current season meant the child was fully vaccinated.

Tricky dosing per ACIP Algorithm: However, there is a subtle pitfall. A single first seasonal influenza vaccine dose prior to July 1, 2019, e.g., in early 2019, is not considered a valid priming dose for this upcoming season. So, in this admittedly uncommon situation, a single dose after July 2019 is not a valid booster dose; it is considered a priming dose, even if the new dose is given in the same 2019 calendar year as the 2018-19 seasonal vaccine dose. Therefore, two doses of 2019-20 seasonal vaccine are now needed to be fully vaccinated for 2019-20. Figure 1.

Improving priming: Two recent publications show that the response to the priming dose is critical to the intensity and diversity of antibody responses. The first from the CDC1 was a meta-analysis of randomized studies measuring hemagglutination inhibition (HAI) antibody response to MF59-adjuvanted inactivated influenza vaccine (a-IIV) versus standard IIV (s-IIV) in children under 72 months old. Against vaccine-matched Type A and B influenza viruses, two a-IIV doses produced higher titers than two doses of standard IIV in children <9 years old; ratios of titers were even higher for those <36 months old. Table 1. Interestingly, one a-IIV dose was equal to two s-IIV doses against Type A viruses. Against vaccine-mismatched A or B strains, a-IIV induced 2.0-2.9 times higher titers than s-IIV. These data indicate better “imprinting” of the immune system in young children with a-IIV.

The second study2 followed up a prior study that showed priming with LAIV (dose 1 = LAIV, boost dose = IIV) instead of IIV (both priming and boosting with IIV) produced higher HAI titers against the variable “head” of influenza’s hemagglutinin molecule at 28 and 90 days after the booster dose. The new study measured antibodies against the conserved “stalk” of the hemagglutinin molecule. Antibodies against the head are type-specific and usually effective only against vaccine-matched strains. Antibodies against the stalk are not type-specific and should convey broader activity, even against mismatched strains. Of note, priming with LAIV induced three times higher ELISA titers against the stalk than priming with IIV. More important, LAIV priming produced neutralizing (inactivates the virus) antibodies, whereas the IIV priming schedule did not.

Take-home messages:

  1. Be careful about when the first dose of vaccine was given to <9-year-olds this year, focusing on the July 1, 2019 date.
  2. Priming is critical for optimizing influenza vaccine responses. The most critical is in those <36 months old. Two-dose IIV schedules, as now recommended, may not be the best use of currently available vaccines. Priming either with an adjuvanted IIV or with LAIV could be novel short-term partial answers to suboptimal responses in children <9 years old until universal vaccines in development are available. Hopefully, in the coming years these novel approaches will be considered by ACIP.

Table 1. Ratios of pooled geometric mean titers (GMT) for HAI antibodies for trivalent/quadrivalent adjuvanted(a)-IIV versus standard(s)-IIV.

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Figure 1. ACIP recommended schedule algorithm for influenzae vaccines in children <9 years old.

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  1. Priming with MF59 Adjuvanted Versus Nonadjuvanted Seasonal Influenza Vaccines in Children – A Systematic Review and a Meta-analysis. Patel MM, Davis W, Beacham L, et al. Vaccine. Available online 15 Nov 2019.
  2. A Live-Attenuated H5N2 Prime-Inactivated H5N1 Boost Vaccination Induces Influenza Virus Hemagglutinin Stalk Specific Antibody Responses. Kongchanagula A, Samnuanb K, Ponthip W, et al. Vaccine Available online 15 Nov 2019.