Reports

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.

PRIORITY PRESS - 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

San Francisco, California / September 12-15, 2009

Since the introduction in 1999 of the 7-valent pneumococcal conjugate vaccine (PCV7) in the US up to 2008, the rate of invasive pneumococcal disease (IPD) among children under the age of 5 has fallen nearly 80% (100 to 23 cases per 100,000), according to statistics collected by the US Centers for Disease Control (CDC). Based on these data, the introduction of a 13-valent PCV (PCV13), which covers many of the non-targeted serotypes now responsible for IPD, will produce a further reduction. It is expected that from previous experience with the PCV7, the reduction in risk of IPD will extend to adults through a herd immunity effect.

“On the basis of potential preventable IPD due to serotypes targeted in the new PCV13 but not targeted in the PCV7 vaccine, we expect the transition to the new vaccine to produce a large further reduction in IPD, perhaps as much as 50%,” stated Dr. Pekka Nuorti, Respiratory Diseases Branch, CDC, Atlanta, Georgia.

Increase in IPD-causing Serotypes

Data from countries that have introduced PCV7 over the last decade, including Canada, demonstrate that most IPD in children is now caused by serotypes not covered in the PCV7. In the US, serotype 19A accounted for 42% of cases in 2007. In Belgium, a new report documented a ninefold increase in 19A serotype IPD over a recent 10-year period with the steepest and most consistent rise occurring after a free national universal PCV7 program was launched in 2007. Similarly, 7F and 1 serotypes not covered in the PCV7 (but that will be covered in the PCV13) also rose steeply over the same period.

“The increase in the non-vaccine serotypes 1, 7F and 19A has partly countered the positive impact of the PCV7,” confirmed Dr. Jan Verhaegan, Laboratory Medicine, University Hospital, Leuven, Belgium. The increase in serotypes 1 and 19A started even before the universal vaccine program was in place, making it difficult to confirm the role of the vaccine as the only factor in the rise of these serotypes. Dr. Verhaegan did note that vaccines that cover these serotypes could be expected to have an important impact on IPD incidence when they are introduced in his country.

Impact on Adults

A similar phenomenon was observed in Denmark, where the incidence of serotype 19A IPD began increasing before the relatively recent introduction of a universal PCV7 program, but adults were most affected even though the vaccinations were administered to children. In adult cases of pneumococcal infection, there was a correlation between mortality and the presence of comorbidities, but half of the deaths occurred in individuals with no comorbidities, reinforcing the importance of childhood vaccination to risk of disease in older individuals. In a study designed to look specifically at this issue, IPD rates were evaluated over 12 years divided into three periods: prior to introduction of the PCV7 vaccination program in children (1997-2000); the early years of PCV7 vaccination program (2001-2004); and several years after the PCV7 vaccination program was in place (2005-2008).

“Relative to the pre-vaccine era, there was a 24% reduction in the PCV7 serotypes among individuals over the age of 65 during the early years of the vaccination program and a 37% reduction in the late years. However, while the non-PCV7 serotypes decreased 16% in the early years, they increased by 62% in the later years,” reported Dr. Josefina Liñares, Department of Microbiology, Hospital de Bellvitge, Barcelona, Spain. This included a doubling of the rates of IPD due to serotype 16A, a more than tripling of the rates of IPD due to serotype 7F and a quintupling of rates of IPD due to serotype 24F.

“It has been previously observed that pediatric vaccination programs reduce disease risk in other age groups, particularly older patients or individuals who are immunologically compromised, but this impact should be more rigorously included in public health calculations,” Dr. Liñares suggested.

The impact on adults may be explained by evidence that carriage rates for non-PCV7 serotypes increase in children even when they do not have active disease. In a national survey on pneumococcal carriage undertaken over a recent two-year period in France, serotype 19A carriage had risen to 10% in a population of PCV7-vaccinated children (97.9% rate of vaccination) 6 to 24 months old who were healthy or presented with acute otitis media (AOM). When assessed for risk factors, recent use of antibiotics increased rates of serotype 19A carriage by almost 50% (HR 1.48; 95% CI, 1.09-2.01; P<0.01). AOM (HR 1.83; 95% CI, 1.1-3.03) and participation in daycare (HR 1.6; 95% CI, 1.17-2.18) also significantly increased risk. In contrast, an older sibling reduced the risk of serotype 19A carriage (HR 0.52; 95% CI, 0.38-0.71). Investigators suggested that the introduction of a vaccine that offers protection against 19A would be expected not only to reduce risk to children but risk of carriage and infection in other age groups.

Clinical Efficacy and Cost-Effectiveness

For disease prevention, clinical efficacy predicts cost efficacy, as demonstrated in a study evaluating the effect of the PC7 in Quebec. Based on data collected from surveillance and administrative databases, approximately 20,000 IPD cases were prevented in children and adults in the year 2006-2007 as a result of the introduction of the PCV7 in 2004, according to a team of investigators that included Dr. Jacques Pépin, Department of Microbiology, Université de Sherbrooke. Based on this rate of infection, the $23 million spent on the vaccination program very closely approximated the calculated $23 million in estimated economic benefits for society. For the health system, the authors calculated an incremental cost-effectiveness ratio of $18,000 per quality-adjusted life-year, which is well within most definitions of cost efficacy.

The cost efficacy of the PCV13 will require real-world data based on changes in infection patterns after this form of disease prophylaxis is introduced, but it will be important to include risk to adults and children as was undertaken in the Quebec study. Due to herd immunity, some of the most significant benefits regarding morbidity and mortality may accrue to the aged or to patients compromised by chronic diseases as has been suggested by increasing rates of 19A serotype IPD in older adults.

The Potential of Immunization at Birth

The introduction of PCV13 should further reduce the risk of IPD. One group that will be left vulnerable is children under the age of 60 days, which precedes the initiation of the multi-dose vaccination schedule. Although pneumococcal infection is an uncommon cause of mortality in infants in Canada and other industrialized countries, pneumococcal colonization can be detected in up to 60% of infections by six weeks in some developing tropical countries, according to Dr. David Goldblatt, Institute of Child Health, University College London, UK, who presented late-breaker data on a program of immunization at birth that was undertaken in Kenya.

“This is the first report of a study of conjugate vaccine given at birth,” observed Dr. Goldblatt, who said the key end point was safety in a study that randomized 300 infants of HIV-positive mothers to PCV7 at birth followed by typical doses in the usual schedule starting at six weeks. While the vaccine was found safe, Dr. Goldblatt was also able to report that carriage rates of the targeted serotypes were lower in early vaccinated infants over the early period of vulnerability. In addition, protective titres for most serotypes were higher at 36 weeks in the early vaccination group relative to the usual schedule group, although the difference was only significant for serotype 4.

“The problem with waiting until six weeks is that you are missing the boat for a significant percentage of children who develop IPD,” Dr. Goldblatt told delegates. Although his research is only an initial step in the process of testing newborn inoculation, the results were promising.

Summary

The introduction of universal vaccination with PCV7 has been a major public health success, but it has allowed rates of non-targeted serotypes to increase. The development of the PCV13, which covers many of the most prominent serotypes that arose following the introduction of PCV7, such as serotype 19A, is expected to provide a substantial additional reduction in the risk of IPD. The benefit is expected not only to accrue to vaccinated children but through herd immunity, to older age groups as well, including the elderly.

Note: At press time, the PCV13 is not available in Canada.