Action And Clinical Pharmacology
Mechanism of Action
Prevnar 13 contains the 7 pneumococcal capsular polysaccharides that are in Prevnar (7-valent) (4, 6B, 9V, 14, 18C, 19F, 23F) plus 6 additional polysaccharides (1, 3, 5, 6A, 7F, 19A) all conjugated to CRM197 carrier protein. B-cells produce antibodies in response to antigenic stimulation via T-dependent and T-independent mechanisms. The immune response to most antigens is T-dependent and involves the collaboration of CD4+ T-cells and B-cells, recognizing the antigen in a linked fashion. CD4+ T-cells (T-helper cells) provide signals to B-cells directly through cell surface protein interactions, and indirectly through the release of cytokines. These signals result in proliferation and differentiation of the B-cells, and production of high-affinity antibodies. CD4+ T-cell signaling is a requisite for the generation of long-lived B-cells called plasma cells, which continuously produce antibodies of several isotypes (with an IgG component) and memory B-cells that rapidly mobilize and secrete antibodies upon re-exposure to the same antigen.
Bacterial capsular polysaccharides (PSs), while varied in chemical structure, share the common immunological property of being largely T-independent antigens. In the absence of T-cell help, PS stimulated B-cells predominantly produce IgM antibodies; there is generally no affinity maturation of the antibodies, and no memory B-cells are generated. As vaccines, PSs are associated with poor or absent immunogenicity in infants less than 24 months of age and failure to induce immunological memory at any age. Conjugation of PSs to a protein carrier overcomes the T-cell–independent nature of PS antigens. Protein carrier-specific T-cells provide the signals needed for maturation of the B-cell response and generation of B-cell memory. Conversion of Streptococcus pneumoniae PSs to a T-cell-dependent antigen by covalent coupling to the immunogenic protein carrier CRM197 enhances the antibody response and induces immune memory. This has been demonstrated to elicit booster responses on re-exposure in infants and young children to pneumococcal polysaccharides.
Infants and Children
Prior to the licensure of 7-valent pneumococcal conjugate vaccine (Prevnar) in Canada in 2001, the observed incidence rates of invasive pneumococcal disease (IPD) among children <2 years of age and <5 years of age were 58.8-112.2 per 100,000 and 35.0-63.8 per 100,000 per year, respectively. The overall fatality rate was 2.0%. The incidence rate of pneumococcal meningitis among children <2 years of age was 9.0 per 100,000 per year, with a case fatality rate of 5.9%.
Since the introduction of Prevnar (7-valent) in Canada in 2001, it has been shown that the incidence of IPD caused by Prevnar (7-valent) serotypes decreased by 92% in Vancouver, 94% in Calgary and by 72% in Quebec.
While the effect of routine use of Prevnar (7-valent) in infants and young children has been dramatic, with a near-total elimination of the serotypes contained in this vaccine, an increase in other serotypes causing IPD has been observed (as an increasing percentage of residual disease). Data from Canadian surveillance systems (National Centre for Streptococcus [NCS]; Immunization Monitoring Program, Active [IMPACT]; and Institut National de Santé Publique du Québec [INSPQ]) showed that serotypes 19A, 6A and 3 have emerged as the predominant pneumococcal serotypes causing IPD in Canadian children, accounting for approximately one-third of the residual IPD in 2007 in children <5 years of age. Compounding the issue of the predominance of emerging serotype 19A is that it is increasingly likely to be nonsusceptible to commonly used first-line antimicrobial agents.
Serotype surveillance of invasive S. pneumoniae performed by the National Microbiology Laboratory in 2010 to establish a baseline serotype distribution in Canada during introduction of Prevnar 13 revealed that serotypes 19A, 7F and 3 were the most common serotypes in children, accounting for 57% of all invasive isolates in <2 year olds, 62% in 2-4 year olds and 45% in 5-14 year olds. Prevnar 13 serotypes represented 65%, 71% and 61% of pneumococci isolated from <2 year olds, 2-4 year olds, and 5-14 year olds, respectively.
Following Prevnar 13 introduction in the Calgary area in mid 2010, the overall pneumococcal nasopharyngeal colonization rate in healthy children declined from 19% in 2003-2006 to 13% in 2010-2012 (p<0.001), and colonization with serotype 19A decreased from 18% of all serotypes in 2010 to 4% in 2012. Children who received 2 or more doses of either Prevnar (7-valent) or Prevnar 13 had reduced odds of colonization with any pneumococcus in adjusted logistic regression (Odds ratio: 0.75; 95% CI: 0.63-0.9).
Prior to the introduction of Prevnar (7-valent) into the National Immunization Program (NIP), the IPD incidence for Canadian adults aged 65 years and older ranged from 16 to 31 per 100,000. A ten-year population-based surveillance of all cases of invasive pneumococcal infection occurring in the Calgary Health Region reported a decrease of 92% in 2007 vs. 1998-2001 in Prevnar (7-valent) serotypes among adults 65 years and older suggesting a herd immunity, a phenomenon that occurs via interruption of transmission of disease to otherwise susceptible populations. However, the incidence of IPD in adults, especially the elderly, has remained high, ranging from 23 per 100,000 to 29.4 per 100,000. Although the incidence estimates among adults younger than 65 are lower than those among adults older than 65, IPD represents a major public health burden among younger adults as well.
Canadian serotype surveillance performed by the National Microbiology Laboratory in 2010 revealed that serotypes 19A, 7F and 3 were the most common serotypes in adults, accounting for 44% of invasive S. pneumoniae isolates in 15-49 year olds, 41% in 50-64 year olds and 36% in ≥65 year olds. Prevnar 13 serotypes represented 60%, 53% and 49% of pneumococci isolated from 15-49 year olds, 50-64 year olds, and ≥65 year olds, respectively.