Pneumococci Transmission Dynamics:

1. Vaccine Serotypes Percent Vaccine Effect 20% bnv V V Timing bvX Pre 98 99 Post 03 04 15% f v V Colonized with both V NV X Not Colonized 10% f nv NV 5% bvNV NV bnv X 0% 19 14 23 6b 9v 18 4 19 6 23 9 1 10 11 12 15 16 17 20 22 3 33 35 38 5 7 8 Vaccine Effect Non Vaccine Serotypes f f c no no no no f b f v PCV7 VR Non-vaccine Serotypes A Mathematical Model for the Impact of the Conjugate Vaccine on S. pneumoniae Vaccine and Non-vaccine serotypes Robertino M Mera MD PhD*, Linda A Miller PhD*, Michael A Pentella PhD***, Thomas R Fritsche MD PhD**, Ronald N Jones MD** * GlaxoSmithKline, Upper Providence, PA. ** JMI Laboratories, North Liberty, IA. *** University of Iowa Hygienic Laboratory, Iowa City, IA Introduction The heptavalent pneumococcal conjugate vaccine (PCV7) has been available since February 2000 and contains polysaccharide conjugate for serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. These seven serotypes accounted for the majority of pediatric as well as adult pneumococcal infections in the pre-licensure era, but represent only a fraction of the 90 known serotypes [1]. Despite initial problems with distribution, the vaccine had reached coverage [2] of 73% for three dosages in children 19-35 months of age by 2004. Several reports [3] revealed substantial decreases in the incidence of invasive pneumococcal disease caused by vaccine serotypes. Despite these successes, there have been conflicting reports as to the impact of the vaccine on antimicrobial resistance. Although penicillin resistance had diminished among invasive isolates, a recent report shows that pneumococcal vaccination did not appreciably change the prevalence of drug-resistant strains of Streptococcus pneumoniae [4]. A compartment transmission mathematical model is introduced in order to understand the changes over time in the serotype proportion and multiple resistance (MR) to antibiotics in the United States. A surveillance study is used to corroborate the insights of the mathematical model. Methods S. pneumoniae transmission dynamics are used to develop a mathematical model that takes into account changes over time among vaccine and non-vaccine serotypes. The results from the mathematical model are then applied to the evaluation of a surveillance study. 704 isolates were sampled from a large dataset generated by a longitudinal surveillance program (SENTRY) from before and after PCV7 introduction. Equal numbers were obtained from the years before (1998-1999) and after (2003-2004) the introduction of the vaccine. The strains originated from the nine US census regions. Age, sex, geographic origin, isolate source, serotype and resistance information were available for the analysis. Multiple resistance is defined as resistance to two or more antibiotic classes; penicillins, macrolides, sulfas, tetracyclines and quinolones. Results Known Facts used to design the mathematical model: Pneumococci Transmission Dynamics: The serotype distribution before and after the introduction of the PCV7 vaccine can be seen below. Among PCV7 serotypes, isolates resistant to only one antibiotic drop by a factor of 5, and they are the ones with the least transmission advantage. Susceptible isolates decrease by a factor of 3, while multiple resistant isolates drop only by a factor of 2, and they are the least affected by the drop in prevalence and the switch process. Transmission of non-vaccine serotypes are favored by the vaccine, and MR isolates have the most transmission advantage, and they increase by a factor of roughly 3.5. Isolates resistant to only one antibiotic increase by a factor of a little more than 2, while isolates susceptible to all antibiotics increase in the post-vaccine period by a little less than 2. This process is more pronounced in children than in adults, and also more noticeable in not-invasive isolates when compared to invasive isolates. The proposed mathematical model, by framing the changes in prevalence of vaccine and non-vaccine serotypes in terms of transmission advantage (or disadvantage) allows us to properly understand the impact of S. pneumoniae conjugate vaccine. • R0 = Colonizing potential of pneumococci • b = transmission rate per unit of time • m = removal rate of hosts from population • f = rate of loss of colonization • v = proportion vaccine serotypes among all isolates • nv = proportion of non-vaccine serotypes Conclusions • In the study population Non Vaccine Serotypes have now the same prevalence that the Vaccine Serotypes had before the introduction of the PCV7 vaccine. • A herd immunity effect in adults has contributed to the serotype switch process. • Non Vaccine Serotypes have acquired multiple resistance at a rate that is proportional to the replacement process. • Vaccine Serotypes have continued to acquire multiple resistance despite the fact that they are less prevalent in the post-vaccine era. • Invasive isolates have experienced both the serotype switch and the increase in multiple resistance, but at a lower rate than middle ear isolates. • Overall multiple resistance will likely continue to increase despite serotype replacement. • References • Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000; 19:187–95. • CDC National Immunization survey, accessed on 5/30/2006 at the URL: http://www.cdc.gov/nip/coverage/NIS/04/toc-04.htm • Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348:1737–46. • Frazao N, Brito-Avo A, Simas C, Saldahna J et al. Effect of the seven-valent conjugate pneumococcal vaccine of Streptococcus pneumoniae in healthy children attending day-care centers in Lisbon. Pediatr Infect Dis J 2005; 24:243-252. • Serotype replacement has to occur for colonization to remain stable •  NV Serotypes =  V Serotypes Due to serotype switch multiple resistance (MR) was just slightly higher in the post vaccine era, 47% vs. 46% than in the pre-vaccine era. Nonetheless, significant changes were observed, mainly with resistance increasing 3.7 times among non-vaccine serotypes, and declining (as a proportion of all serotypes) among VS from 39% to 21%. See graph below. Structure of the mathematical model: Pre 1998 - 1999 Post 2003 - 2004 39% 40% Status Susceptible Any one non-S 30% Two or more R 30% 26% Bars show percents 21% 20% Percent 17% 20% 15% 10% • Pneumococcal vaccine does not change the Colonization Rate among vaccinated children or the whole population so: CR1998 = CR2004 • Vaccine serotypes are replaced by non-vaccine serotypes in vaccinated children and their contacts. • The coverage for 3 doses of PCV7 in the US was 73.2 % in 2004; 68.1% in 2003; 40.8% in 2002. Insights from the mathematical model: 7% 7% 10% 6% • Non-vaccine serotypes will replace vaccine serotypes among vaccinated and non-vaccinated children for a given vaccine coverage until an equilibrium is reached. • Among vaccine serotypes, susceptible isolates will have the most transmission disadvantage, followed by single resistant isolates. 2% NV PCV7 NV PCV7 Serotype Serotype