Reports

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PRIORITY PRESS - 28th Annual Meeting of the European Society of Pediatric Infectious Diseases (ESPID)

Nice, France / May 4-8, 2010

Protection against invasive pneumococcal disease (IPD) afforded by immunization with the 7-valent conjugate pneumococcal vaccine (PCV7) has been well documented in many countries, particularly the US. PCV7 was made available in the US following a 37,868-patient Kaiser Permanente trial showing 97% efficacy against targeted serotypes; as a result, the PCV7 vaccine has become the standard of care in numerous national immunization campaigns.

According to Prof. Paolo Bonanni, Department of Hygiene and Epidemiology, University of Florence, Italy, however, serotypes responsible for a major proportion of pneumococcal disease have changed as a result of widespread use of the PCV7 vaccine. “IPD remains the leading cause of early childhood mortality and morbidity globally and the emergence of new serotypes continues to challenge prevention programs in every country.” Prof. Bonanni said. In reviewing evidence in favour of mass immunization against IPD, Prof. Bonanni noted that in Canada, the introduction of routine infant immunization with PCV7 reduced the incidence of IPD in children under the age of 2 years by over 81%. In Norway, the incidence of IPD declined by 95% in children under 2 years of age following the introduction of PCV7, although replacement serotypes represent a new cause for concern. In addition, infection with the seven serotypes contained in the PCV7 vaccine has declined in the UK from 300 cases a year to fewer than 20 cases a year following introduction of the three-dose infant vaccination regimen.

Still, as Prof. Bonanni pointed out, pneumococcal disease remains a worldwide concern because of replacement disease. “We are seeing the incidence of 19A reaching 20% to 40% in many countries,” he related, “and in the Canadian province of Quebec, serotypes 19A, 7F and 15B are reaching unprecedented levels.”

Measuring Vaccine Efficacy

Prof. David Goldblatt, University College London Institute of Child Health, UK, noted that serology studies have become accepted by most regulatory bodies as surrogates of vaccine efficacy. The internationally agreed correlate of protection for the vaccine as a whole is an aggregate for all serotypes of 0.35 µg/L.

Yet new data from the UK for serotype 6B showed that the correlate of protection may be as low as 0.2 µg/L for some serogroups, suggesting that antibody levels of 0.2 µg/L following vaccination may be an effective measure of protection, as Dr. Goldblatt noted.

The Centers for Disease Control in the US have essentially endorsed this observation in its advisory statement on the efficacy of the PCV13 vaccine. However, according to Dr. Goldblatt, opsonophagocytic activity (OPA) of antibodies to Streptococcus pneumoniae serotypes may be a better measure of disease protection than serum IgG concentrations. In vitro OPAs of serum antibodies are believed to represent the functional activities of antibodies in vivo and thus correlate with protective immunity.

A double-blind, nine-centre randomized UK trial recently examined OPA titres following 2+1 immunizations with either PCV7 or PCV13. Blood samples taken immediately following vaccination showed the PCV13 group had 87% to 100% OPA titres =1.8 for all 13 serotypes, although they dropped to <50% for serotypes 4, 18C, 19F and 19A by 12 months. Following the booster dose, OPA titres increased again from 93% to 100% for all serotypes. Importantly, OPA geometric mean concentrations were heavily weighted in favour of PCV13 vs. PCV7, with a mean of 6703 in the PCV13 group vs. 304 in the PCV7 cohort.

Researcher Dr. Bernard Fritzell, Paris, France, presented an overview of 13 clinical trials comparing 4729 PCV13-treated infants to 2760 recipients of PCV7. The aggregate data demonstrated that PCV13 shares a comparable safety profile to PCV7, which has been administered to more than 300 million children worldwide. “All these studies have shown that the two [vaccines] exhibit no statistically significant differences in terms of the incidence of injection-site reactions [with significant tenderness exhibited in around 10% of both groups], fever, sleep or appetite changes or irritability following vaccination,” Dr. Fritzell said. “The safety profile of PCV13 is not affected by administration with other routine infant immunizations [either].”

Other Study Findings

A pivotal study of PCV13’s efficacy was carried out in a trial against a new PCV10 agent in a 1:1 randomization of 300 infants. In this pivotal study, PCV13 showed improved or equivalent efficacy against 12 of the 13 serotypes of current concern. When measured against serotype 6B, PCV13 provided protective serum OPA titres one month post-vaccination to the 1:8 level in 90% of infants compared with 80% for PCV10 recipients. PCV13 also demonstrated more modest but higher efficacy than PCV10 against serotypes 1, 3, 5 and 7F.

Dr. Emmanuel Grimpel, Paediatric Hospitalization Unit, Armand Trousseau Hospital, Paris, recently directed a 1:1 randomized trial examining the safety and efficacy of transitioning children from an initial schedule of PCV7. “The answer seems to be that PCV13 can be substituted at any point, since both agents share the same protection against PCV7-covered serotypes and share almost identical safety profiles,” Dr. Grimpel reported. They also examined how many doses of the PCV13 vaccine are necessary to extend protection against new disease serotypes. The analysis found that administration of the PCV13 booster after one year of age spiked antibody levels to non-PCV7 serotypes in nearly 100% of recipients to highly protective antibody titres. “A single booster dose at one to two years in life confers broadly extended protection,” Dr. Grimpel confirmed.

Emerging Vaccination Programs

This year’s ESPID sessions featured numerous reports on emerging vaccination programs worldwide.

A Chinese study assessed the potential health-cost benefits of routine vaccinations of infants under the age of 2 years with PCV13 vs. no vaccination. Under lead author Dr. Kenneth Lee, School of Pharmacy, Chinese University of Hong Kong, investigators concluded that this campaign cost an additional $34 (US) per child but prevented 1534 severe infant illnesses in a population of 7 million at an average potential cost of $2144 per case. “Our study suggests that PCV13 vaccination is highly cost-effective overall,” Dr. Lee concluded

Another study in Turkey examined a total of 202 invasive S. pneumoniae isolates and found that PCV7’s coverage rates of 70% were increased by 22.7% with the PCV13 vaccine vs. 9% with PCV10.

A parallel study in Brazil conducted from 1999 to 2008 highlighted the rising incidence of 6B serotypes to a level of 52.3% of isolates. The São Paolo group’s findings suggest that the PCV13 vaccine might prevent 96.6% of IPD cases in their region vs. 92.1% for PCV10.

Summary

Widespread vaccination against pneumococcal disease with the original PCV7 vaccine was an undisputed public health success but it has led to the emergence of now more common serotypes that are responsible for increasing proportions of IPD worldwide. The new 13-valent pneumococcal vaccine contains an additional six serotypes and it can be expected to further decrease the incidence of IPD by as much as 50%. It is now up to pediatricians to advocate for its use in appropriate age groups to ensure the incidence of the disease does not increase due to the continued emergence of non-vaccine serotypes.