Pneumococcal conjugate vaccine in adults: Let's see what happens.

The recent recommendation for the use of the 13-valent pneumococcal conjugate vaccine (PCV13) in adults 65 y of age and older, provides a new tool for preventing disease in this at-risk population. The conjugate vaccine induces a T-cell dependent response, which distinguishes it from the polysaccharide vaccine and could provide the longer-term protection necessary to have a significant impact in this population.

Pneumococcal conjugate vaccine use in adults.

Streptococcus pneumoniae is a leading cause of illness and death in adults. A polysaccharide vaccine has been available for over 30 years, but despite significant use, the public health impact of this vaccine has been limited. The 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed by the US Food and Drug Administration and other international regulatory authorities with the assumption that induction of a T cell-dependent immune response and noninferior immunogenicity to vaccine antigens when compared with the polysaccharide vaccine would be important to satisfy a significant unmet medical need. PCV13 efficacy against vaccine-type pneumococcal community-acquired pneumonia was confirmed in a large randomized controlled trial in older adults and its use is now increasingly recommended globally.

Distribution of 13-valent pneumococcal conjugate vaccine Streptococcus pneumoniae serotypes in US adults aged ≥50 years with community-acquired pneumonia.

BACKGROUND: Streptococcus pneumoniae causes a substantial proportion of community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) in the United States. Limited data are available regarding the pneumococcal serotypes causing CAP and HCAP. METHODS: Adults aged ≥ 50 years presenting to participating US hospitals with radiographically confirmed pneumonia between February 2010 and September 2011 were screened for inclusion. S. pneumoniae was identified using microbiological cultures, BinaxNOW® S. pneumoniae assay, or urine antigen detection (UAD) assay capable of detecting 13-valent pneumococcal conjugate vaccine (PCV13)-associated serotypes. RESULTS: Among 710 subjects enrolled, the median age was 65.4 years; 54.2% of subjects were male, 22.4% of radiographically confirmed pneumonia cases were considered HCAP, and 96.6% of subjects were hospitalized. S. pneumoniae was detected in 98 subjects (13.8%) by any test, and PCV13-associated serotype(s) were identified by UAD in 78 (11.0%). Serotype 19A was most prevalent, followed by 7F/A, 3, and 5. Serotypes associated with 7-valent pneumococcal conjugate vaccine (PCV7) accounted for 25% of UAD-positive isolates. CONCLUSIONS: Pneumococcal serotypes causing noninvasive pneumonia in adults may differ significantly from those causing invasive disease, with PCV7-associated serotypes overrepresented. Serotype 5, rarely seen in contemporary surveillance of invasive disease in the United States, substantially contributed to the observed cases of S. pneumoniae-positive CAP or HCAP.

Immune response to 13-valent pneumococcal conjugate vaccine with a reduced dosing schedule.

BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV7) has demonstrated effectiveness against pneumococcal illnesses when administered as 3 infant doses plus a toddler dose (3+1 schedule) or as an abbreviated schedule of 2 infant doses plus a toddler dose (2+1 schedule). The 13-valent pneumococcal conjugate vaccine (PCV13) is approved and World Health Organization-prequalified for administration in a 2+1 schedule when used as part of routine immunization programs. OBJECTIVE: To summarize immunologic responses elicited by PCV13 administered in a 2+1 schedule and following 2 doses in a 3+1 schedule. METHODS: Studies were double-blind, randomized, active-controlled, multicenter studies except the Mexico study (open-label, single-arm). In 2+1 studies, PCV13 was administered at 2, 4, and 12 (UK) or 3, 5, and 11 (Italy) months. In 3+1 studies (Spain and Mexico), assessment was made postdose 2 of the primary series (2, 4, and 6 months). The primary immunogenicity endpoint was the proportion of participants achieving serotype-specific antipolysaccharide immunoglobulin (Ig)G concentrations ≥ 0.35µg/mL (i.e., responders) 1 month postdose 2. Pneumococcal IgG geometric mean concentrations (GMCs), opsonophagocytic activity (OPA), and concomitant vaccine responses were assessed. RESULTS: PCV13 and PCV7 elicited comparable immune responses for the 7 common serotypes after 2 infant doses. The proportion of PCV13 responders postdose 2 was >85% for most of the 7 common and 6 additional serotypes, except common serotypes 6B (27.9-81.4%) and 23F (55.8-77.5%) and additional serotypes 3 (73.8-96.9%) and 6A (79.2-94.4%). Serotypes 6B and 23F elicited lower IgG GMCs postdose 2 compared with other serotypes; all serotypes demonstrated boosting posttoddler dose. All serotypes demonstrated functional activity; >95% of participants achieved OPA levels ≥ 1:8 postdose 2. Concomitant vaccine responses were similar between PCV13 and PCV7 groups. CONCLUSION: Immune responses elicited by PCV13 following 2 infant doses support transition from PCV7 to PCV13 in countries using a 2+1 schedule.

Pneumococcal conjugate vaccine for adults: a new paradigm.

A 13-valent pneumococcal conjugate vaccine has been studied in adults aged ≥ 50 years to compare the immune response to that induced by the 23-valent pneumococcal polysaccharide vaccine, which has been the standard of care over the past 30 years. The results demonstrate that adults, regardless of whether they are naive or previously vaccinated with the polysaccharide vaccine, have an overall superior antibody response when vaccinated with the conjugate vaccine compared with the pneumococcal polysaccharide vaccine. More importantly, the nature of the response is indicative of a T-cell-dependent response that elicits immunological memory and, therefore, primes the immune system for either natural exposure or subsequent booster vaccination with either conjugate or polysaccharide vaccine. The conjugate vaccine, which has been successful in reducing pneumococcal disease in children, now provides a new approach to preventing pneumococcal disease, including community-acquired pneumonia, in adults.

Advances in pneumococcal disease prevention: 13-valent pneumococcal conjugate vaccine for infants and children.

A 13-valent pneumococcal conjugate vaccine (PCV13), developed with the same chemistry used for the 7-valent PCV vaccine (PCV7) and with the goal of expanding serotype coverage, was clinically evaluated in the United States and Europe and found to induce capsular-specific antibody responses comparable to those of PCV7 for the common serotypes, with robust responses to the 6 additional serotypes. In addition, PCV13 has a similar safety profile to PCV7 and can be given routinely to infants and children, ideally as a 3-dose primary series in the first year of life, with a booster dose in the second year. Children who have initiated their vaccination program with PCV7 can transition to PCV13 at any point in the schedule. Children aged ≥15 months who have been completely vaccinated with PCV7 can receive a single dose of PCV13 to induce immunity to the 6 additional serotypes.

Essential criteria for evaluation of pneumococcal conjugate vaccine candidates.

In 2003, the World Health Organization recommended a concentration of enzyme-linked immunosorbent assay (ELISA) immunoglobulin G (IgG) anti-capsular antibody of 0.35 microg/mL as a reference value that correlates to protection against invasive pneumococcal disease. This threshold can be used to demonstrate immunologic non-inferiority of a new vaccine in comparison trials that use pneumococcal conjugate vaccines (PCVs) as a comparator. An investigational 13-valent PCV (PCV13) compared with seven-valent PCV (PCV7) demonstrated that all of the pneumococcal serotypes contained in PCV13 were immunogenic, with 88-98% of vaccinees achieving antibody concentration > or = 0.35 microg/mL for serotypes shared with PCV7 and >96% for six additional serotypes.

Immunology of combining CRM(197) conjugates for Streptococcus pneumoniae, Neisseria meningitis and Haemophilus influenzae in Chilean infants.

We evaluated the immunogenicity and safety of an investigational combination of 9-valent pneumococcal conjugate vaccine (PCV9) and meningococcal group C conjugate (MnCC) vaccine (PCV9-MnCC) administered concomitantly with Haemophilus influenzae type b (Hib) conjugate vaccine, and of a combination of the three vaccines mixed together as a single injection (Hib-PCV9-MnCC), and compared them to separately administered PCV9 and MnCC dispensed to Chilean infants at 2, 4, and 6 months of age. The frequency of adverse events was similar among groups. Recipients of PCV9 alone or in combination with the other vaccines mounted significant antibody responses to the nine pneumococcal serotypes in PCV9, with >88% achieving protective levels of > or =0.35microg/mL. For serotypes 6B, 9V, and 5, recipients of PCV9 alone had significantly higher geometric mean concentrations (GMCs) than those of the other vaccine groups. Similarly, the GMC of anti-PRP antibodies was significantly lower among recipients of Hib-PCV9-MnCC than among those who received Hib vaccine separately from PCV9 or MnCC. In Chilean infants, PCV9, PCV9-MnCC, and Hib-PCV9-MnCC were highly immunogenic and safe. Overall, interactions of PCV9, MnCC and Hib affected the magnitude (GMC) of the primary antibody responses to some of the antigens, but not the percentage of subjects who achieved protective antibody thresholds.

Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies.

Estimates of minimum protective antibody concentrations for vaccine preventable diseases are of critical importance in assessing whether new vaccines will be as effective as those for which clinical efficacy was shown directly. We describe a method for correlating pneumococcal anticapsular antibody responses of infants immunized with pneumococcal conjugate (PnC) vaccine (Prevenar) with clinical protection from invasive pneumococcal disease (IPD). Data from three double blind controlled trials in Northern Californian, American Indian and South African infants were pooled in a meta-analysis to derive a protective concentration of 0.35 microg/ml for anticapsular antibodies to the 7 serotypes in Prevenar. This concentration has been recommended by a WHO Working Group as applicable on a global basis for assessing the efficacy of future pneumococcal conjugate vaccines. The WHO Working Groups anticipated that modifications in antibody assays for pneumococcal anticapsular antibodies would occur. The principles for determining whether such assay modifications should change the protective concentration are outlined. These principles were applied to an improvement in the ELISA for anticapsular antibodies, i.e. absorption with 22F pneumococcal polysaccharide, which increases the specificity of the assay for vaccine serotype anticapsular antibodies by removing non-specific antibodies. Using sera from infants in the pivotal efficacy trial in Northern California Kaiser Permanente (NCKP), 22F absorption resulted in minimal declines in pneumococcal antibody in Prevenar immunized infants but significant declines in unimmunized controls. Recalculation of the protective concentration after 22F absorption resulted in only a small decline from 0.35 microg/ml to 0.32 microg/ml. These data support retaining the 0.35 microg/ml minimum protective concentration recommended by WHO for assessing the efficacy of pneumococcal conjugate vaccines in infants.

Establishing government-operated vaccine programs: an industry perspective.

During 2000-2002, shortages of numerous routinely administered pediatric vaccines occurred. The reasons for these shortages were varied, but they included policy, manufacturing, and regulatory issues. The use of government manufacturing programs has been proposed as a way to stabilize the fragile vaccine supply and to prevent periodic shortages. Although such programs might be useful for defense needs, it is likely that such an approach would have limited value for routinely administered vaccines. Each of the vaccine components would require a dedicated manufacturing facility, and many components are administered in combination vaccines. Timing is also an important consideration. The restarting of an idled manufacturing facility would take many months; in addition, it often takes nearly 12 months to produce and release a single lot of vaccine. Finally, government-owned programs would face the same issues of regulatory changes, technological advancements, and facility updates as non-government-owned programs do--all of which would require sustained operation and investment. A secure and stable vaccine supply is best built by establishing the importance and value of our vaccine programs, which would, in turn, provide incentives to manufacturers to build capacity and inventories.

Strengthening the supply of routinely recommended vaccines in the United States: recommendations from the National Vaccine Advisory Committee.

Between late 2000 and the spring of 2003, the United States experienced shortages of vaccines against 8 of 11 preventable diseases in children. In response, the Department of Health and Human Services requested that the National Vaccine Advisory Committee (NVAC) make recommendations on strengthening the supply of routinely recommended vaccines. The NVAC appointed a Working Group to identify potential causes of vaccine supply shortages, develop strategies to alleviate or prevent shortages, and enlist stakeholders to consider the applicability and feasibility of these strategies. The NVAC concluded that supply disruptions are likely to continue to occur. Strategies to be implemented in the immediate future include expansion of vaccine stockpiles, increased support for regulatory agencies, maintenance and strengthening of liability protections, improved communication among stakeholders, increased availability of public information, and a campaign to emphasize the benefits of vaccination. Strategies requiring further study include evaluation of appropriate financial incentives to manufacturers and streamlining the regulatory process without compromising safety or efficacy.

Recent progress in the development of vaccines for infants and children.

Infectious agents do not respect national or international boundaries. Attempts to prevent their spread, and the diseases which they cause, involve implementing vaccination as widely and as appropriately as possible. The principles of vaccination against infectious agents are now being applied to cancer and other non-infectious conditions. In order to understand where modern vaccinology is heading, it is necessary to first examine individual components. This brief overview examines the following: Streptococcus pneumoniae, Neisseria meningitidis, varicella zoster, measles, rotavirus, HIV, influenza, "emerging" viral infections and cancer.