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PRIORITY PRESS - 48th Annual Meeting of the Infectious Diseases Society of America

Vancouver, British Columbia / October 21-24, 2010

Universal vaccination programs for children using the 7-valent conjugated pneumococcal vaccine PCV7, initiated in British Columbia and Alberta in 2002 and in the rest of Canada in 2005, have resulted in a decline in disease burden and a corresponding reduction in antibiotic use. However, the benefits of the vaccine have since been eroded by a phenomenon known as serotype replacement. Although there are nearly 100 serotypes of S. pneumoniae, PCV7 was effective against most of the antibiotic-resistant types. Over time, several drug-resistant serotypes not covered by PCV7 have increased in frequency.

“The 7-valent vaccine has had an amazing effect in terms of controlling what were the most frequent serotypes causing invasive disease,” noted Dr. Julie A. Bettinger, Assistant Professor of Pediatrics, Vaccine Evaluation Centre, University of British Columbia, Vancouver, here at IDSA. “In Alberta and BC, which are the 2 provinces that have been using the 7-valent vaccine the longest, we don’t even see 7-valent-preventable cases anymore.”

Changing Epidemiology

However, since PCV7 use began, the occurrence of several serotypes has increased markedly, particularly serotype 19A, which accounted for 0% to 5% of cases in Canadian provinces prior to PCV7 and now represents 6% to 31%, the highest percentage being found in Quebec. By 2008-2009, serotype 19A was responsible overall for 44% of invasive pneumococcal disease (IPD) in children <5 years of age. In the same period, infections due to penicillin-resistant strains of 19A have also increased, as have cases of multi-drug-resistant infections, which were first seen in 2005.

Research conducted by Dr. Anne Wormsbecker, Mount Sinai Hospital, Toronto, Ontario, revealed changes in the epidemiology of IPD in children <5 years old since the PCV7 program began. Following an initial sharp decline in cases, the infection rate has steadily increased since 2006, and now stands at 77% of pre-PCV7 levels. Most cases are due to serotypes, primarily 19A, covered by a new PCV13 vaccine. However, 44% of infections were caused by serotypes not covered by any current conjugate vaccine. According to Dr. Wormsbecker, among other changes, the newly predominant strains seem to cause more pneumonia, and less bacteremia and meningitis, than before. “We’re not entirely sure why,” she told delegates, “but it seems that the strains that are around appear to have more of a predilection for pneumonia and even complicated pneumonias than the previous strains.” She also identified increasing resistance to macrolides and amoxicillin, and noted that ceftriaxone resistance was identified in a 19A isolate last year.

Dr. Wormsbecker recommended changing to the PCV13 vaccine and suggested that a catch-up program for pre-schoolers would be beneficial.

Projected Disease Rates

The Healthy People (HP) program in the US sets 10-year objectives relating to a wide range of health issues. The HP 2010 targets for IPD incidence—46 cases per 100,000 children under 5 years and 42 cases per 100,000 adults 65 and over—were met largely thanks to the introduction of the PCV7 vaccine, reported Dr. Cynthia Whitney, Centers for Disease Control and Prevention, Atlanta, Georgia.

The program has created projections for 2020 based on a model assuming the replacement of PCV7 with PCV13, and including 3 scenarios. The minimum replacement scenario assumes that non-PCV13 serotype disease will continue to behave as it did from 2000 to 2008, i.e. remain at low levels. The most replacement scenario assumes that non-PCV13 serotypes will increase in a similar fashion to that seen in PCV13-only serotypes (19A, etc.) during 2000-2008. The base case assumes that non-PCV13 serotypes will increase at 50% of the most replacement scenario rate. The most, base and minimum scenarios predict rates of 14, 12 and 9 cases per 100,000 children under 5, respectively (Figure 1). The proposed US target rates for HP 2020 are 12 cases per 100,000 children under 5 and 31 cases per 100,000 adults of 65 and older.

Dr. Whitney warned that these projections are based on a simple model that makes a number of assumptions about the response of IPD to the new vaccine. In addition, changes in risk factors and interventions may affect the predictions. “There’s a good chance we’re going to have new vaccine formulations in use by 2020 and there are a lot of efforts to decrease smoking, both direct and indirect exposure to smoke. On the other hand, we’re also seeing a big increase in diabetes over the last few years, so these interventions and risk factors could really change the amount of pneumococcal disease,” she told delegates.

Figure 1. IPD Rate in Children <5 Years of Age

PCV13 Adult Vaccination

Despite the use of the polysaccharide vaccine PPSV23, together with the herd effect benefits of PCV7 usage in children, older adults continue to experience substantial disease burden due to pneumococcal infections. Researcher Dr. David Strutton, Collegeville, Pennsylvania, presented a model that investigated the potential improvement that could be achieved by replacing PPSV23 with the PCV13 vaccine in the adult US population aged 50 and older. In the model, the predicted effectiveness of PCV13 was based on PCV7 data from children. Another assumption made was that PPSV23 reduces the risk for IPD but not for non-bacteremic pneumonia (NBP).

Based on revaccination with PCV13 every 10 years vs. vaccination with PPSV23 according to current guidelines, the model predicted lifetime reductions as follows: IPD, 81,000; NBP, 3,954,000; deaths, 232,000; total costs, $10.2 billion. Dr. Strutton acknowledged that current data for PCV13 in adults show a non-significant trend towards reducing pneumonia in even immunocompromised individuals. “There will be data in the future from a large trial that is currently looking at that, but we don’t have that data yet,” Dr. Strutton told IDSA delegates, “so that’s a very important consideration, maybe the most important consideration out of this.”

Reduced Vaccine Schedules

The optimal scheduling for PCV7 is considered to be a series of 3 doses 2 months apart during infancy, followed by a booster in the second year of life (3+1 regimen). However, because of cost issues and the number of injections that must be given to infants, more than 50% of countries have adopted 3-dose regimens (2+1 and 3+0).

Here at IDSA, Dr. Ron Dagan, Pediatric Infectious Disease Unit, Ben-Gurion University of the Negev, Soroka University Medical Center, Beer-Sheva, Israel, discussed research he conducted into the implications of the reduced vaccination regimens. He found considerable variation in antibody titres in response to differing regimens among the 7 serotypes covered by the vaccine. In some cases, the antibody titres produced were identical for both 3+1 and 2+1 regimens, although others, particularly serotype 6B, were significantly lower prior to the booster shot. The 3+0 regimen produced a good response initially, as would be expected, but ended poorly at 18 months compared to the other 2. A catch-up regimen (0+2 at 12 and 18 months) ultimately yielded better responses than the other regimens, although without providing coverage during the first year of life.

However, protection against disease did not necessarily mirror titre levels. At 24 months, hospital admissions due to lower respiratory tract disease was the same for both 3+1 and 2+1 patients; outpatient visits were similar throughout the first 2 years of life. IPD declined rapidly in countries using either 3+1 or 2+1 regimens. Importantly, total pneumococcal carriage was very similar for either regimen, and only slightly higher for 0+2. “Reduction of carriage is the most difficult end point to achieve,” stated Dr. Dagan, “and it is the number one most responsible for herd immunity.” He concluded that the 2+1 regimen provided high levels of both individual and herd protection, but that 3+1 might provide a faster method to eliminate vaccine-susceptible serotypes.

Dr. Dagan then cited a study from Fiji that demonstrated a significant response from just 1 vaccination at 14 weeks. He suggested that at least part of the immune response might be due to activation of B-cells, which is not reflected in measured titre levels. In conclusion, he suggested, “The number of vaccinated children may be more important than the number of doses given per child.”