A century of pneumococcal vaccination research in humans.

Sir Almroth Wright coordinated the first trial of a whole-cell pneumococcal vaccine in South Africa from 1911 to 1912. Wright started a chain of events that delivered pneumococcal vaccines of increasing clinical and public-health value, as medicine advanced from a vague understanding of the germ theory of disease to today's rational vaccine design. Early whole-cell pneumococcal vaccines mimicked early typhoid vaccines, as early pneumococcal antisera mimicked the first diphtheria antitoxins. Pneumococcal typing systems developed by Franz Neufeld and others led to serotype-specific whole-cell vaccines. Pivotally, Alphonse Dochez and Oswald Avery isolated pneumococcal capsular polysaccharides in 1916-17. Serial refinements permitted Colin MacLeod and Michael Heidelberger to conduct a 1944-45 clinical trial of quadrivalent pneumococcal polysaccharide vaccine (PPV), demonstrating a high degree of efficacy in soldiers against pneumococcal pneumonia. Two hexavalent PPVs were licensed in 1947, but were little used as clinicians preferred therapy with new antibiotics, rather than pneumococcal disease prevention. Robert Austrian's recognition of high pneumococcal case-fatality rates, even with antibiotic therapy, led to additional trials in South Africa, the USA and Papua New Guinea, with 14-valent and 23-valent PPVs licensed in 1977 and 1983 for adults and older children. Conjugation of polysaccharides to proteins led to several pneumococcal conjugate vaccines licensed since 2000, enabling immunization of infants and young children and resultant herd protection for all ages. Today, emergence of disease caused by pneumococcal serotypes not included in various vaccine formulations fuels research into conserved proteins or other means to maximize protection against more than 90 known pneumococcal serotypes.