Supported by an unrestricted educational grant from Wyeth-Ayerst Laboratories

Volume II, Issue 6 - February 1999

Current Status of Pneumococcal Vaccines

S. pneumoniae, first identified by Pasteur in 1881, was shown to be the most common cause of lobar pneumonia following discovery of the Gram stain in 1884. Major medical discoveries in the first half of the twentieth century advanced our understanding of the pathobiology of pneumococcal infections including the chemical structure and antigenicity of pneumococcal polysaccharide, the antiphagocytic role of polysaccharide capsule in human disease and its association with virulence, as well as the protective effect of specific antipolysaccharide antibody.

By 1940, 80 capsular serotypes had been described. The number has risen to approximately 90 currently. There has been remarkable stability of serotypes over time as well as a predominant role for relatively few serotypes in most disease (Table 1). Serotype predominance does vary by country and continent, however.

Efforts to develop effective pneumococcal vaccines began as early as 1911, spurred on by recognition of the modest effect of antiserum on treatment of pneumococcal disease in the pre-antibiotic era. With the advent of penicillin in the 1940s, interest in vaccine development waned until many patients were observed to die or suffer severe sequelae despite antibiotic treatment. Vaccine development was rejuvenated by the late 1960s. In 1977 the first polyvalent (14-valent) pneumococcal vaccine was licensed in the United States (US). This vaccine contained serotype specific antigens of the 14 most common pneumococcal strains isolated from patients in the US. The 14-valent vaccine was supplanted in 1983 with licensure of the currently used 23-valent vaccine.

Despite availability of this safe and effective pneumococcal polysaccharide vaccine (PPV), over 500,000 cases of invasive pneumococcal disease occur annually in the US with deaths in excess of 40,000. Recommendations for use of PPV have been limited to individuals who, because of older age or existing medical conditions are known or expected to have increased risk for pneumococcal infection or to have excessive morbidity or mortality following infection with S. pneumoniae. Implementation of recommendations has been suboptimal and overall incidence of disease has not decreased. Severe pneumococcal infections continue to occur, both in candidates for PPV who have failed to be immunized, and in healthy individualsÛespecially childrenÛwho are not candidates for the current PPV. Despite and probably in a significant way because of burgeoning development and pervasive use of potent orally administered antibiotics during the last quarter century, our ability to effectively treat pneumococcal infections has, if anything, diminished. Increasing resistance of pneumococci to a variety of antimicrobial agents in vitro and clinically has intensified interest in development of more effective pneumococcal vaccines for all age groupsÛespecially for children.

Epidemiology of Colonization and Disease

Pneumococci are ubiquitous, colonizing the nasopharynx of 15% to 60% of individuals. The prevalence depends on age, season, crowding, and presence of viral upper respiratory tract infection. Reported colonization rates are also dependent on the sensitivity of the culture method utilized. Pneumococci, probably spread from person to person by respiratory droplets, are truly normal flora. The vast majority of individuals acquire successive serotypes of S. pneumoniae, are colonized for weeks to months, and remain asymptomatic. The most frequently colonizing serotypes are generally the same serotypes that cause mucosal and invasive infection (Table 1). Secondary invasive disease within a family or epidemic disease is rare, except in an extraordinary scenario such as when rapid passage of a more virulent strain occurs in conditions of extreme crowding, poor ventilation, and increased host susceptibility such as in nursing homes and mines. Disease usually follows rapidly upon acquisition of a new serotype rather than after prolonged carriage and is clearly enhanced by significant respiratory tract viral illnesses such as influenza. Among young children who acquire a new pneumococcal serotype in the nasopharynx, illness (usually acute otitis media) occurs in approximately 15%, usually within 1 month of acquisition. There is a direct association between increasing type-specific serum antibody and protection from invasive disease (including pneumonia) but the effect of antibody on pneumococcal colonization and upper respiratory tract infection has not been found to be linear. Individuals immunized with PPV, for example, develop serum concentrations of antibodies that protect against disease but have unaltered nasopharyngeal colonization patterns.

Each 0.5 mL dose of PPV contains 25 µg of each purified antigen (Table 1) with either thimerosal or phenol as a preservative. PPV is administered by intramuscular or subcutaneous injection. Currently licensed PPVs contain 23 serotypes of S. pneumoniae that account for 88% of the episodes of bacteremia and meningitis in adults. In addition, cross-reactivity from several capsular types covers an additional 8% of bacteremic disease. PPVs include nearly 100% of antigens correlating with serotypes that cause bacteremia and meningitis in children and 85% of serotypes that cause acute otitis media.

Most healthy adults who receive PPV develop antibodies against serotypes contained in the vaccine, usually within 2 or 3 weeks after immunization. Elderly adults and persons with some chronic illnesses may not respond as well, if at all. As with other polysaccharide vaccines, healthy children younger than 2 years of age have limited response to most serotypes. This lack of response is a significant problem since 80% of childhood pneumococcal disease occurs in this age group. Immature response to PPV is still demonstrable to some degree to 5 years of age and is especially important for serotypes 6B, 14, 19F and 23F, which are common causes of pediatric infections and are the most prevalent penicillin-resistant serotypes.

There is not a reliable serologic marker for protection against pneumococcal disease. Clinical studies of PPV have resulted in various estimates of effectiveness in individuals immunized after 2 years of age. Overall, the vaccine prevents 60% to 70% of invasive disease in adults. The effectiveness of pneumococcal vaccine has also been demonstrated in older children who have an increased incidence of invasive pneumococcal disease. Compared with nonimmunized children, immunized children with sickle cell disease or children who had undergone splenectomy have experienced significantly less bacteremic pneumococcal disease. Data are inadequate to assess effectiveness in preventing otitis media in children older than 2 years. An important concern at the time PPV was licensed was the possible ability of vaccine to shift the epidemiology of disease-producing serotypes. However, general use of vaccine has not been associated with an increased prevalence of invasive disease due to nonvaccine serotypes.

Approximately half of individuals given pneumococcal vaccine have mild side effects such as erythema and pain at the injection site. Less than 1% may develop fever, myalgia, or severe local reactions. Serious side effects such as severe allergic reactions have been reported in about 5 in every million doses given.

Recommendations for immunization of children 2 years of age or older are shown in (Table 2). The unifying principle is that vaccine should be administered to persons who have increased risk of acquiring invasive pneumococcal infection (including pneumonia) or increased risk of severe disease if they become infected. There are additional circumstances to consider (Table 3). For persons who are to be immunized before splenectomy, cancer chemotherapy, or immunosuppression vaccine should be given at least 2 weeks prior, if possible, for optimal response. Immunization during radiation or chemotherapy often results in poor antibody response. Patients who were immunized during these therapies should be reimmunized 3 months after discontinuation of the therapy.

Adolescent patients, parents, and other caregivers of immunized children with anatomic or functional asplenia must be informed that immunization does not guarantee protection from fulminant pneumococcal disease. Patients and parents must continue vigilance for febrile illnesses and seek prompt medical attention. Antimicrobial prophylaxis may be indicated for certain persons following immunization.

Reimmunization after 3 to 5 years is recommended for children 10 years of age or younger who are at high risk of severe pneumococcal infection (Table 4) using the same 0.5 mL dose as given initially. Reimmunization is not associated with a significant increase in reactions when implemented in the manner recommended.

Pneumococcal vaccine can be given concurrently with other vaccines without diminishing immunogenicity or augmenting reactions to any of the vaccines.

Minor illnesses such as upper respiratory tract infections are not contraindications to immunization. Persons with moderate to severe illness should not be immunized until their condition improves. A serious allergic reaction to a dose of pneumococcal vaccine or a vaccine component is a contraindication to further doses. Immunization during pregnancy should generally be avoided because the effect on the fetus is unknown. However, individuals who are at high risk of pneumococcal disease during pregnancy and who are otherwise candidates for vaccine must weigh relative risks. Then immunization is usually justified.

Although PPV has significantly reduced morbidity and mortality in those immunized, shortcomings include <80% protection against invasive disease in healthy recipients over 2 years of age, lack of immunogenicity in the most vulnerable age group (<2 years), suboptimal immunogenicity in immunocompromised individuals, lack of effect on nasopharyngeal S. pneumoniae colonization and modest, if any, effect on pneumococcal otitis media and sinusitis. Sustained S. pneumoniae virulence, increasing resistance to antimicrobial agents, suboptimal vaccine, and less than ideal implementation of recommended immunization of high-risk groups highlight the urgent need for improved pneumococcal vaccines for potentially universal use in infants.

Conjugate vaccines consist of a capsular saccharide covalently bound to a carrier protein. These vaccinesÌ development brought about the remarkable near elimination of Haemophilus influenzae type b (Hib) disease in children following introduction of universal immunization in infancy with a variety of Hib conjugate vaccines. Many pneumococcal conjugate vaccines (PCVs) have been developed and are under study. The basic strategy is similar for all PCVs. Vaccine content is manipulated to convert the T-cell independent response (of which young children are incapable) to a T-cell dependent response (of which infants are capable) by covalently binding the relevant polysaccharide to a protein. The candidate PCVs have different carrier proteins, methods of conjugation, and molecular size of the saccharides. All contain less antigen by weight than PPV. To date, the carrier proteins have been the same ones used for Hib conjugate vaccines. Since each serotype-specific pneumococcal antigen must be conjugated separately with the carrier protein, there are limits (because of total carrier protein content) to the possible number of serotypes included in any PCV. An additional consideration is the potential for antigenic competition that could occur with increasing numbers of admixed saccharide-protein components, potentially resulting in blunted or aberrant immunologic responses. Table 5 contrasts PPVs with PCVs.

Since serologic markers for protection against disease are still lacking, clinical efficacy trials involving huge numbers of individuals are required to assess vaccines. There are currently clinical efficacy trials in the US, Finland, South Africa, and Gambia using 7-valent and 9-valent vaccines (See Table 1 for serotypes included), in 3-dose primary schedules beginning at 6 to 8 weeks of age (and some with a booster dose), with a variety of outcomes targeted for measurement (e.g., invasive disease and episodes of otitis media, pneumonia, and serotype-specific otitis media). Safety has been excellent, with mild local or febrile reactions that did not increase with subsequent vaccine doses. Preliminary results are available from a randomized, double-blind trial involving approximately 38,000 California children 15 months of age or younger. Half of the infants received a heptavalent PCV (7 pneumococcal saccharides each covalently bound to a mutant diphtheria protein) and half received a control vaccine (meningococcal protein conjugate vaccine). Vaccines were given at 2, 4, and 6 months of age with a booster at 12 to 15 months. The PCV was 100% effective against invasive disease caused by vaccine serotypes and 90% effective against invasive disease when all pneumococcal serotypes were considered. Data regarding protection against clinical episodes of acute otitis media will be available when analysis of the trial results is complete.

Additional small studies have suggested PCVs may also have better immunogenicity than PPVs in HIV-infected individuals less than and greater than 2 years of age, in individuals greater than 2 years of age with sickle cell disease, and in certain individuals with recurrent respiratory tract illnesses who have suboptimal response to PPV. Additionally, PCVs appear to significantly reduce nasopharyngeal colonization with vaccine serotypes, creating a biologically plausible link to possible reduction of pneumococcal otitis media and sinusitis. Fast track to licensure and universal implementation of PCVs in infamcy are expected. Additionally, in children older than 2 years, PCVs are likely to induce a better response than the currently licensed PPVs.

If subsequent trials and analyses go as expected, the potential for eliminating one of the most formidable bacterial pathogens of the human race will be at hand.

Suggested Reading

0. MMWR 1991;40 (RR-12):41-44.
1. American Academy of Pediatrics 1997 Red Book. Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: The Academy; 1997:410-9.
2. Clin Infect Dis 1992;14:801-9.
3. Concise Rev Pediatr Infect Dis 1998;9:823-4.
4. J Infect Dis 1996;174:127-8
5. J Pediatr 1996;128:649-53.
6. J Pediatr 1998;133:275-8.
7. N Engl J Med 1991;325:1453-60.
8. Pediatr Infect Dis 1998;17:685-91.
9. Pediatrics 1997;99:575-80.
10. Pediatrics 1998;101:604-11.
11. Pediatrics 1998;102:538-45.
12. Vaccine Bull 1998;119:2.

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