Disease Risk – Pneumococcal disease

 

Risk to a child from Pneumococcal disease if not vaccinated until after the age of 5:

Streptococcus pneumoniae, also called pneumococcus, can cause invasive pneumococcal diseases (IPD) such as pneumonia and meningitis.  90 serotypes have been identified [1].  The PCV-7 pneumococcal conjugate vaccine (brand name “Prevnar”) was licensed in 2000 to target 7 serotypes of pneumococcus [1].  Pneumococcal serotypes compete with each other.  The introduction of the vaccine has decreased the incidence of IPD from the 7 serotypes targeted by the vaccine but conversely has increased IPD from non-vaccine pneumococcal serotypes.

Pneumococcal serotypes also compete with Hib, Staphylococcus aureus (“staph”), and other bacteria in the nasal passages which can be carried on an asymptomatic basis.  A study found that a reduction in vaccine-targeted pneumococcal serotypes is associated with an increase in staph [2].  Other studies found an increase in staph-related ear infections associated with the PCV-7 vaccine [3] [4].  One study discusses whether the current increase in severe community-acquired staph infections (MRSA, “Methicillin-resistant Staphylococcus aureus”) is partially caused by the introduction of the PCV-7 vaccine, and states that the answer is yet to be determined [3].  There is inter-species competition between pneumococcus and Hib [5], and a recent study have shown increases in the proportion of Hib and Moraxella catarrhalis bacteria in the middle-ear fluid of PCV7-immunized children [6].

 

Factors Not Considered: PCV-13 was licensed in 2010 to target 13 pneumococcal serotypes.  It is unclear whether it will result in other non-targeted pneumococcal serotypes to become more invasive, as was the experience with the PCV-7 vaccine [7].  There is also the potential that the PCV-13 vaccine may further increase staph and Hib colonization in nasal passages. It is too early to assess the incremental disease risk if not vaccinated with PCV-13, so this analysis only addresses incremental risk if not vaccinated with the PCV-7 vaccine.

Incidence Rates: After just a few years in the American market, initial studies of Prevnar’s impact [7][8] reported reductions of more than 60% in IPD cases and hospitalizations in children by 2004. The annual rate of hospitalization for invasive pneumococcal disease among children <5 years decreased from an average of 27.2 admissions/100,000 population during 1998–1999 to 10.1 admissions/100,000 population in 2004 [7]

However after an initial drop, the incidence rate stabilized and then began increasing as nonvaccine serotypes became more prolific.  Studies in Massachusetts [8][9][10] indicates that IPD (invasive pneumococcal disease) per 100,000 children under age 5 dropped from 53.1 in 1991 in the pre-vaccine era to 19.0 in 2001-2002 after the vaccine was fully implemented, but then increased to 24.8 in 2006-2007.  IPD from vaccine serotypes decreased to zero in 2006-2007, but IPD from non-vaccine serotypes increased to the 24.8 per 100,000 incidence rate.  The study covering the 2001-2007 years discussed that “Although we have learned that IPD incidence has stabilized in the PCV7 era, continued surveillance is necessary to learn whether the overall incidence of IPD in Massachusetts children is increasing. Incidence of disease caused by PCV7 serotypes has reached zero but overall incidence of IPD might increase if incidence of IPD caused by non-PCV7 serotypes continues to escalate.”[9].

Recent studies in Dallas [11] and Cleveland (Jacobs et al, 2008) [12] also indicate that incidence rates are rising due to nonvaccine serotypes.  Dallas rates of IPD in children fell by more than half from 1998 to 2003, but as the non-vaccine strains emerged, the overall IPD rate began increasing and reached three quarters of the pre-Prevnar rate by 2008. The Cleveland study showed growth rates from 100% to as high as 900% in the non-vaccine serotypes over a seven year period.

Mortality Rates: Despite the changes in incidence rate, overall mortality rate in children has not changed from the pre-vaccine era to the post-vaccine era.  In the most comprehensive investigation, one that covered a population of 19 million people in and around 8 major cities before and after the introduction of the PCV-7 vaccine, the study found that “the overall mortality rate among children did not change during the study period”.  The decrease in mortality rate due to vaccine serotypes was completely offset by the increased mortality rate due to nonvaccine serotypes.  The case fatality rate for children aged < 5 years increased both for disease due to vaccine serotypes and for disease due to nonvaccine serotypes, thus offsetting the reduction in incidence rates and keeping the mortality rate constant at 0.6 deaths per 100,000 children.[7]

Rates of Long Term Sequelae or Injury: Pneumococcal meningitis dropped from 3.6 per 100,000 children < age 5 in 1991 to an average of 1.3 in 2001-2003, but has since remained consistent through 2006-2007 [8][9][10].  According to a study in Massachusetts over the 2001-2007 study period, there were no significant changes in the proportion of IPD attributable to pneumonia, meningitis, bacteremia associated with upper respiratory tract infection, and bacteremia without focus.[9]

Long-term sequelae from pneumococcus include hearing loss, neurological deficit, mental retardation, seizure disorder, and motor deficits. The long-term sequelae rate ranges in studies from 36% in The Netherlands [13], 41% in Denmark [14], 52.6% in Taiwan [15], to 49% in Bangladesh [16].  For the purposes of this analysis, the average of those four percentages (45%) will be used.

Incremental Risk in Population with Low Rates of Vaccination (if a child does not vaccinate by age 5): The mortality rate of 0.6 per 100,000 children under age 5 has remained constant from the pre-vaccine era to the post-vaccine era.  Therefore, the incremental risk of death if not vaccinated until age 5 is zero.  The pneumococcal meningitis incidence rate per 100,000 children under age 5 in the pre-vaccine era and post-vaccine era was 3.6 and 1.3, respectively.  Using an average percentage of long-term sequelae of 45%, the cumulative incremental risk of permanent injury if not vaccinated until age 5 is 0.51 per 10,000 or 1 in 19,500.

Incremental Risk in Highly Vaccinated Population (if a child does not vaccinate by age 5): The mortality rate of 0.6 per 100,000 children under age 5 has remained constant from the pre-vaccine era to the post-vaccine era.  Therefore, the incremental risk of death if not vaccinated until age 5 is zero.  The pneumococcal meningitis incidence rate of 1.3 per 100,000 children under age 5 in the post-vaccine era has stabilized because disease from nonvaccine serotypes has replaced disease from vaccine serotypes.  This means that the risk of pneumococcal meningitis in a highly vaccinated population is due to the nonvaccine serotypes, and is the same risk for unvaccinated and vaccinated children.  Therefore, the cumulative incremental risk of permanent injury if not vaccinated until age 5 is zero.

 

References:

[1] Centers for Disease Control and Prevention: Epidemiology and Prevention of Vaccine-Preventable Disease. Atkinson W, Wolfe S, Hamborsky J, McIntyre L. eds. 11th edition. Washington D.C.: Public Health Foundation, 2009.

[2] Lochay et al. Association between Carriage of Streptococcus pneumoniae and Staphylococcus aureus in Children.  JAMA. 2004;292(6):716-720. doi: 10.1001/jama.292.6.716

[3] Yochay et al. Interference between Streptococcus pneumoniae and Staphylococcus aureus: In Vitro Hydrogen Peroxide-Mediated Killing by Streptococcus pneumoniae. Journal of Bacteriology, July 2006, p. 4996-5001, Vol. 188, No. 13. 0021-9193/06/$08.00+0 doi:10.1128/JB.00317-06
[4] Bogaert. Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. Lancet. 2004 Jun 5;363(9424):1871-2.

[5] Lysenko ES, Ratner AJ, Nelson AL, Weiser JN (2005) The Role of Innate Immune Responses in the Outcome of Interspecies Competition for Colonization of Mucosal Surfaces. PLoS Pathog 1(1): e1. doi:10.1371/journal.ppat.0010001

[6] Revai et al. Effect of Pneumococcal Conjugate Vaccine on Nasopharyngeal Bacterial Colonization During Acute Otitis Media. PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1823-1829 (doi:10.1542/peds.2005-1983)

[7] Hicks LA, Harrison LH, Flannery B, Hadler JL, Schaffner W, Craig AS, Jackson D, Thomas A, Beall B, Lynfield R, Reingold A, Farley MM, Whitney CG. Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004. J Infect Dis. 2007;196(9):1346-54.

[8] Hsu K, Pelton S, Karumuri S, Heisey-Grove D, Klein J; Massachusetts Department of Public Health Epidemiologists. Population-based surveillance for childhood invasive pneumococcal disease in the era of conjugate vaccine. Pediatr Infect Dis J. 2005;24(1):17-23.

[9] Hsu KK, Shea KM, Stevenson AE, Pelton SI; Massachusetts Department of Public Health. Changing serotypes causing childhood invasive pneumococcal disease: Massachusetts, 2001-2007. Pediatr Infect Dis J. 2010;29(4):289-93.

[10] Loughlin AM, Marchant CD, Lett SM. The Changing Epidemiology of Invasive Bacterial Infections in Massachusetts Children, 1984 through 1991. Am J Public Health. 1995 March; 85(3): 392-394.

[11] Techasaensiri, C et al. Epidemiology and Evolution of Invasive Pneumococcal Disease Caused by Multidrug Resistant Serotypes of 19A in the 8 Years After Implementation of Pneumococcal Conjugate Vaccine Immunization in Dallas, Texas. Pediatric Infectious Disease Journal: April 2010 – Volume 29 – Issue 4 – pp 294-300

[12] Jacobs, MR et al. Emergence of Streptococcus pneumoniae Serotypes 19A, 6C, and 22F and Serogroup 15 in Cleveland, Ohio, in Relation to Introduction of the Protein-Conjugated Pneumococcal Vaccine. Clin Infect Dis. (2008) 47 (11): 1388-1395. doi: 10.1086/592972

[13] Kornelisse RF, Westerbeek CM, Spoor AB, et al: Clin Infect Dis. 1995

Dec;21(6):1390-7

[14] Ostergaard C, Koradsen HB, Sauelsson S: BMC Infectious Diseases 2005, 5:93

[15] Ma JS, et al: J Microbiol Immunol Infect 2002;35(1):23-8

[16] Saha, SK et al.  Neurodevelopmental Sequelae in Pneumococcal Meningitis Cases in Bangladesh: A Comprehensive Follow-up Study. Clinical Infectious Diseases 2009; 48:S90-6