The volatile nature of pneumococcal serotype epidemiology: potential for misinterpretation.

In the last 25 years, the development of conjugate vaccines against the most common bacterial pathogens in childhood has been one of the most significant public health advances. With the development of Haemophilus influenzae type b conjugates, we saw the virtual eradication of Hib disease in the United States. Hib vaccines were targeted to the “b” serotype, which accounted for almost all diseases, and fortunately with the use of these vaccines, serotype b disappeared and there was no emergence of the other serotypes of Haemophilus influenza to fill this void. This success led to the development of conjugate vaccines for the prevention of pneumococcal disease. At the outset, this story was more complicated because there were more than 90 known serotypes and at least 7 serotypes, depending on the country, required in a vaccine to protect against the majority of disease. With the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in 2000, we saw a dramatic reduction in disease due to the 7 serotypes in the vaccine. However, following introduction of this vaccine, in many (but not all) settings, we have seen increases in the amount of disease due to serotypes not in the vaccine. This phenomenon has been referred to as “replacement” implying that these increases were caused by the vaccine. It should be noted that this “replacement” for invasive disease has only been seen in uncontrolled observational studies. In addition, a review of pneumococcal epidemiology over time reveals a history of the emergence and decline of different serotypes in the absence of vaccine use. It is the purpose of this article to review this history and to discuss the multiple possible causes of changes in pneumococcal serotype epidemiology. Early studies of pneumococcal conjugate vaccines in randomized clinical trials revealed that while carriage of vaccine strains decreased dramatically, carriage of nonvaccine serotypes increased proportionately so that overall carriage rates remained essentially unchanged. In other words, there was 100% replacement by nonvaccine serotypes. However, since not all serotypes are equally capable of causing disease, the impact on disease risk was not known until randomized controlled vaccine efficacy trials were conducted. Increases in the incidence of nonvaccine serotype pneumococcal disease were first seen in the Finnish Otitis Media trial. Although a 57% reduction of vaccine serotype disease was seen, there was a concomitant increase of 33% in nonvaccine serotypes in vaccines. By contrast, no significant replacement was seen for invasive disease in the California, American Indian, or South African studies that were randomized controlled trials. At that point, many experts felt that this lack of replacement was possibly the result of the relatively low coverage rates in the populations in these trials. However, given that the vaccinated children in the these trials experienced replacement colonization with nonvaccine serotype strains, the lack of any observed replacement invasive disease in these trials is notable and difficult to explain if vaccines were the primary driver of replacement. Following vaccine introduction in 2000, the US Centers for Disease Control and Prevention ABC surveillance system began to observe increases in the incidence of serotype 19A both in both age groups targeted for vaccination and some age groups not targeted for vaccination with pneumococcal conjugate vaccine. The incidence of 19A increased over time especially in HIV-infected populations. More recently, data on surveillance for meningitis increases in the incidence of serotype 19A as well as 22F and 35B were seen. Pelton et al have reported increases in the incidence of otitis media due to serotype 19A in Massachusetts. A dramatic increase in the incidence of 19A disease was also reported in the Yukon River delta in Alaska as well as in Spain. The story would seem clear at this point that introduction of PCV7 led to replacement disease. However, the story is more complicated than that. The pneumococcal epidemiology of several populations in the world has been studied extensively. Long-term studies reveal extensive variability in the distribution of serotypes causing disease. A good example is the study by Fenoll et al who reviewed the seroepidemiology of pneumococcal disease in Spain between 1970 and 1996. In these prevaccine years, a 2.5-fold increase in the rate of serogroup 19 disease was seen. Similar increases were observed for other serogroups while a greater than 2-fold drop was seen for serogroup 1. This variability is illustrated