Pneumococcal Vaccine: The Good, the Bad, and the Uncertain

Conjugated pneumococcal vaccine works, but pockets of disease remain.

The introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in the U.S. in 2000 was a welcome addition to our preventive armamentarium; however, questions remain regarding the degree of protection in immunized children with fever or pneumonia. Two studies examined recent trends in invasive pneumococcal infection.

In the first study, researchers used data from the Nationwide Inpatient Sample to evaluate discharge diagnoses in more than 35 million hospital admissions before (1997–1999) and after (2001–2004) routine immunization with PCV7 in the U.S. Among children younger than 2 years, admissions for pneumonia decreased by 39% overall and by 65% for pneumonia attributed to Streptococcus pneumoniae.

In the second study, investigators analyzed serotypes of colonization and invasive pneumococcal disease (IPD) from 1995 through 2006 in highly immunized children younger than 2 years in Alaska. During the first years after introduction of routine PCV7 (2001–2003), Native Alaska children had a dramatic (67%) decrease in IPD, but the decrease was followed by an 82% increase from 2003 through 2006. The increase was due to non-PCV7 serotypes, most commonly 19A. Non–Native Alaska children had a sustained decrease in IPD.

Comment: Although PCV7 clearly has had an effect on invasive pneumococcal infections in the pediatric population, pockets of at-risk children exist, such as the Native Alaska children in this study and, as previously reported, some children in Salt Lake City. In addition, anecdotal reports have been circulating about an increased incidence of infections with non-vaccine S. pneumoniae strains 1, 3, and 19A in other parts of the country. We must continue to be vigilant in the evaluation of all febrile children and children with pneumonia, regardless of immunization status. When invasive pneumococcal disease is identified, isolates should be typed and sent to public health laboratories so we may better understand the evolving epidemiology.

— Peggy Sue Weintrub, MD

 Published in Journal Watch Pediatrics and Adolescent Medicine May 23, 2007Citation(s): Grijalva CG et al. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: A time-series analysis. Lancet 2007 Apr 7; 369:1179-86.

HPV Vaccination: Data at Last

The short-term results of a three-dose immunization schedule are impressive for many recipients. As for the long term: Still unclear.

The quadrivalent human papillomavirus (HPV) vaccine was released to much fanfare and political wrangling last year based on data from an early analysis of two giant industry-sponsored, blinded, placebo-controlled phase III trials. Updates from these ongoing studies have now been published.

More than 5000 women worldwide (age range, 16–24) were enrolled in the first study; about 27% had prevaccination evidence of genital infection with a vaccine serotype. After a mean follow-up of almost 3 years, the rates of vaccine-type vulvar, vaginal, and perianal lesions (including warts, precancerous lesions, and cancer) were significantly lower among vaccine recipients without evidence of prior infection, as were the rates of cervical intraepithelial neoplasia (CIN) grades 1–3 and cervical adenocarcinoma in situ. An intention-to-treat analysis of all lesions in all subjects found that the vaccine reduced the incidence of vulvar, vaginal, or perianal lesions by 34%, regardless of HPV type, and reduced incidence of cervical lesions by 20%, regardless of HPV type.

A second study focused specifically on high-grade cervical lesions. After a mean 3-year follow-up of more than 12,000 women, the vaccine was 95%–98% protective against grade 2 or 3 CIN or adenocarcinoma in situ associated with vaccine-type HPV among women without prior evidence of infection; among all women, including those with evidence of prior infection, vaccine efficacy was 44%. Side effects were limited to local reactions and a single episode of vaccine-induced bronchospasm.

Comment: The bottom line seems clear: If women are immunized prior to natural infection with pathogenic HPV serotypes, this vaccine effectively protects them from developing precancerous lesions caused by vaccine strains and presumably protects from cancer as well. The duration of vaccine protection is still unknown. Editorialists point out that, given the biological complexity of HPV-associated disease and the charged political overtones of this vaccine, the practical, ethical, legal and financial challenges of incorporating it into clinical practice will be legion.

— Abigail Zuger, MD

Published in Journal Watch General Medicine May 9, 2007 Citation(s): Garland SM et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007 May 10; 356:1928-43.


Efficacy and Safety of the Quadrivalent HPV Vaccine

Two randomized controlled trials provide an additional year of follow-up.

Anogenital infection with human papillomavirus (HPV) causes both genital warts and cervical cancer in women; HPV types 16 and 18 are responsible for approximately 70% of cervical cancers worldwide. A three-dose quadrivalent vaccine (HPV types 6, 11, 16, and 18) was licensed in the U.S. in June 2006, based partly on interim results from two manufacturer-sponsored, prospective, placebo-controlled trials. Now, investigators report longer-term results from those trials.

The first trial involved 5455 women aged 16 to 24 in 16 countries. Analyses performed approximately 2.5 years after the vaccine series was completed showed the vaccine to be 100% efficacious in preventing anogenital intraepithelial lesions or warts (0 vs. 60 cases), as well as cervical intraepithelial neoplasia grades 1–3 or adenocarcinoma in situ (0 vs. 65 cases), caused by vaccine-type HPV. In an intention-to-treat analysis, the vaccine’s efficacy in reducing the incidence of cervical lesions caused by all HPV types was 20% (344 vs. 421 cases). Vaccine recipients had a slightly higher incidence of local (87% vs. 77%) and mild febrile reactions (13% vs. 10%) than did placebo recipients.

In a similarly designed trial involving 12,167 women aged 15 to 26 years, investigators assessed the vaccine’s ability to reduce the incidence of HPV-16/18–related high-grade cervical neoplasia in participants who were still HPV-16/18–negative 1 month after receiving the third vaccine dose. The primary composite endpoint encompassed cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, and invasive carcinoma of the cervix. Approximately 2.5 years after the third injection, the vaccine showed 98% efficacy in preventing the primary endpoint (1 vs. 42 cases). Intention-to-treat analysis showed a vaccine efficacy of 44% in preventing high-grade HPV-16/18–associated cervical neoplasia (83 vs. 148 cases) and 17% in preventing all high-grade cervical neoplasias (219 vs. 266 cases). The vaccine did not appear to alter disease course in women with existing HPV-16/18 infection. Vaccine recipients again had a slightly higher incidence of local reactions than did placebo recipients; no adverse effects were noted for pregnancies occurring in temporal proximity to immunization.

Comment: Interim results from these two trials provided some of the primary evidence supporting vaccine licensure. Given the relatively short follow-up period even in the present studies, we do not know the duration of protection or the overall benefit afforded by the vaccine in preventing neoplastic disease from subsequent infection. Additionally, as editorialists note, given the vaccine’s high cost and lack of efficacy in women with previous HPV-16/18 infection, optimal use will be either among 11- and 12-year-old girls (a group not enrolled in the studies) or through targeted immunization of populations likely to be HPV-16/18–naive.

— Richard T. Ellison III, MD

Published in Journal Watch Infectious Diseases May 9, 2007

Replacement of Pneumococcal Serotypes After PCV7 Vaccination

Since the introduction of the pneumococcal conjugate vaccine, initial reductions in invasive pneumococcal infections among Alaska Native children have been eroded by an increase in nonvaccine-serotype infections.

The introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in the U.S. in 2000 was followed by a sharp reduction in the rate of invasive pneumococcal disease (IPD) in young children (see Journal Watch Infectious Diseases May 23 2003). This vaccine contains just 7 of >90 known serotypes, but these 7 serotypes have been estimated to cause 80% to 85% of IPD in children.

To measure the effects of PCV7 vaccination, researchers conducted longitudinal population-based laboratory surveillance from 1995 through 2006 for IPD among Alaska Native children <2 years old, a group known to have a high IPD rate. Routine PCV7 immunization began in 2001 in this population. More than 90% of these children receive 3 doses of PCV7 — a rate significantly higher than that for non-Hispanic white Alaska children or for the overall U.S. population of the same age.

In 2001–2003, the PCV7-serotype IPD rate was 92% lower — and the overall IPD rate was 67% lower — than in 1995–2000. In 2004–2006, however, the overall IPD rate increased by 82% compared with 2001–2003. This increase was associated with a 130% rise in the rate of non–PCV7-serotype IPD. Serotype 19A accounted for 28% of the nonvaccine-serotype cases in 2004–2006.

Comment: These findings demonstrate replacement of PCV7 serotypes with nonvaccine serotypes, particularly 19A, which also has increased in other populations. Such figures, from an especially vulnerable population, demonstrate the need for continued surveillance and for development of pneumococcal vaccines with additional serotypes.

— Robert S. Baltimore, MD

Published in Journal Watch Infectious Diseases May 2, 2007

Citation(s):

Singleton RJ et al. Invasive pneumococcal disease caused by nonvaccine serotypes among Alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA 2007 Apr 25; 297:1784-92.

Measles-Mumps-Rubella and Varicella Vaccine Responses in Extremely Preterm Infants

OBJECTIVE. Extremely preterm infants mount lower antibody responses than term infants to several vaccines. The objective of this study was to measure the immunogenicity of measles-mumps-rubella and varicella vaccines in preterm and term children.

METHODS. Immune status before immunization and immune response after immunization with measles-mumps-rubella and varicella vaccines at 15 months of age were compared in 32 infants, 16 of whom were preterm (<29 weeks' gestation) and 16 of whom were term ( 37 weeks' gestation) at birth. Blood was drawn before vaccination and 3 to 6 weeks thereafter. Measles antibody was measured by plaque reduction neutralization assay. Mumps and rubella immunoglobulin G were measured in available sera by enzyme-linked fluorescent immunoassay. Varicella immunoglobulin G was measured in available sera by glycoprotein enzyme-linked immunosorbent assay. Values that were above or below the assay limits were assigned values double or half those limits, respectively. The primary outcome was the geometric mean antibody titer.

RESULTS. Preterm children had lower mumps and rubella geometric mean titers than did term children before vaccine, and nearly all children were seronegative for each of the 4 vaccine antigens before immunization. Measles, mumps, rubella, and varicella geometric mean titers were similar between groups after vaccine. All children were seropositive for measles after vaccine, whereas 13 of 14 preterm and 11 of 13 term children were seropositive for mumps, 13 of 14 preterm and 13 of 13 term children were seropositive for rubella, and 11 of 16 preterm and 9 of 15 term children were seropositive for varicella.
 
CONCLUSIONS. Preterm children mounted antibody responses that were similar to those of term children after measles-mumps-rubella and varicella vaccines at 15 months of age.( Pediatrics 119: E574-E579)

Immunopathology of RSV infection: prospects for developing vaccines without this complication

Respiratory syncytial virus is the most important cause of lower respiratory tract infection in infants and young children. RSV clinical disease varies from rhinitis and otitis media to bronchiolitis and pneumonia. An increased incidence of asthma later in life has been associated with the more severe lower respiratory tract infections. Despite its importance as a pathogen, there is no licensed vaccine against RSV. This is due to a number of factors complicating the development of an effective and safe vaccine. The immunity to natural RSV infection is incomplete as re-infections occur in all age groups, which makes it challenging to design a protective vaccine. Second, the primary target population is the newborn infant, which has a relatively immature immune system and maternal antibodies that can interfere with vaccination. Finally, some vaccines have resulted in a predisposition for exacerbated pulmonary disease in infants, which was attributed to an imbalanced Th2-biased immune response, although the exact cause has not been elucidated. This makes it difficult to proceed with vaccine testing in infants. It is likely that an effective and safe vaccine needs to elicit a balanced immune response, including RSV-specific neutralising antibodies, CD8 T-cells, Th1/Th2 CD4 T-cells and preferably secretory IgA. Subunit vaccines formulated with appropriate adjuvants may be adequate for previously exposed individuals. However, intranasally delivered genetically engineered attenuated or vectored vaccines are currently most promising for newborns, as they are expected to induce a balanced immune response similar to that elicited to natural infection and not be subject to interference from maternal antibodies. Maternal vaccination may be the optimal strategy to protect the very young infants. (Reviews in Medical Virology, Volume 17, Number 1, January 2007, pp. 5-34(30)