Fractional Doses of Pneumococcal Vaccine Could Bolster Supply in Under-Resourced Regions

Immunogenicity from a 40% fractional dose of 13-valent pneumococcal conjugate vaccine (PCV13, Pfizer) was found noninferior to full dose, in immunization of infants in a randomized trial1 in Kenya that also assessed a 10-valent vaccine (PCV10, GSK) and lower fractional doses of both.

Katherine Gallagher, PhD, faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, United Kingdom, and colleagues explain that even with the current, but transitory subsidy, the $2-3 cost per dose of pneumococcal vaccine (given in a 3-dose series) is the most expensive component of the routine immunization schedule in many of the 47 WHO-designated low- and lower-middle income countries.

"The sustainability of the pneumococcal vaccine program is in question in countries that are transitioning out of Gavi (the Vaccine Alliance) support and taking on the full cost of procuring the vaccine," Gallagher and colleagues indicate. "Furthermore, for middle-income countries that are ineligible for Gavi support, a reduction in the cost of the pneumococcal conjugate vaccine may enable vaccine introduction in areas where it is currently unaffordable."

The investigators compared the immunogenicity associated with full dose, 40% and 20% fractional doses of each vaccine, in a 2 primary and 1 booster series, to over 2,000 infants randomly assigned to the 6 treatment conditions; and to a 7th group, all of equal size, that received the PCV10 full dose as 3 primary doses without booster.

The principal measure of immunogenicity was serum IgG to vaccine-type capsular polysaccharides, from blood samples drawn 4 weeks after the 3rd dose, when the infants were approximately 10 months of age. ”The samples were analyzed for IgG to all vaccine serotypes; except for samples from the 3- full dose PCV10 series, which were assayed for 7 vaccine serotypes, due to study funding restraints. In addition, a subgroup of 50 randomly selected samples were tested for functional antibodies.

"Serum IgG has worked well as a correlate of protection for vaccine licensure purposes," Gallagher explained, in discussing the trial with Contagion. "The first trials of PCVs measured serum IgG and disease endpoints and the data from these trials are what generated a correlate of protection among infants—a threshold of IgG above which risk of IPD (invasive pneumococcal disease) was minimal."

The threshold value of IgG may not remain the index of vaccine effectiveness, however, as Gallagher pointed out that protection against pneumococcal carriage and invasion of pneumococci into sterile sites is a complex biological process.

"It is likely to be a surrogate marker for other immune actors that are active at the mucosa. As such, as newer PCVs are licensed and elicit lower IgG, but non-inferior responses, it is unclear whether these PCVs will be as protective or will have attenuated protection," Gallagher suggested.

The investigators reported that the 40% fractional dose of PCV13 met the noninferiority criterion for 12 of 13 serotypes after the primary series, and for 13 of 13 after the booster. Neither the 20% dose of PCV13 nor the 40% or 20% fractional doses of PCV 10, however, met that threshold. Vaccine serotype-type carriage prevalence was similar across the PCV13 groups at 9 and 18 months of age.

The children found to have received subtherapeutic vaccine dosage were subsequently immunized, Gallagher noted. "The children who were allocated to receive doses that did not reach our non-inferiority criterion were traced and revaccinated with a full dose.We managed to trace 91% of these participants."

In addition, Gallagher pointed out, "the risk of vaccine type IPD in our community is low given the high coverage of the routine immunization program. Additionally, these children will have now aged-out of the highest risk period for IPD, which is infancy."

The trial findings support off-label use of the 40% fractional PCV13 dosing to help sustain pneumococcal vaccine immunization programs. In addition, Gallagher hopes that the findings, along with lower cost full dose products from alternative sources such as the Serum Institute of India (SII), prompt the principle vaccine manufacturers to further reduce their prices for under-resourced regions.

"This (price reduction) would be easier for them than changing their manufacturing volumes to meet the lower demand, if fractional doses were to be implemented across multiple countries," she said. "I doubt they will invest in re-labeling their product at this stage to re-license a lower dose."

Reference

1.Gallagher KE, Bottomley LC, Kaniu M, et al. Fractional doses of pneumococcal conjugate vaccine—A noninferioritytrial. N Engl J Med 2024; Published online September 26: DOI:10.1056/NEJMoa2314620. https://www.nejm.org/doi/full/10.1056/NEJMoa2314620