Development Of Pneumococcal Conjugate Vaccines Research Articles

Pneumococcal Vaccines: Past Findings, Present Work, and Future Strategies.

The importance of Streptococcus pneumoniae has been well established. These bacteria can colonize infants and adults without symptoms, but in some cases can spread, invade other tissues and cause disease with high morbidity and mortality. The development of pneumococcal conjugate vaccines (PCV) caused an enormous impact in invasive pneumococcal disease and protected unvaccinated people by herd effect. However, serotype replacement is a well-known phenomenon that has occurred after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) and has also been reported for other PCVs. Therefore, it is possible that serotype replacement will continue to occur even with higher valence formulations, but the development of serotype-independent vaccines might overcome this problem. Alternative vaccines are under development in order to improve cost effectiveness, either using proteins or the pneumococcal whole cell. These approaches can be used as a stand-alone strategy or together with polysaccharide vaccines. Looking ahead, the next generation of pneumococcal vaccines can be impacted by the new technologies recently approved for human use, such as mRNA vaccines and viral vectors. In this paper, we will review the advantages and disadvantages of the addition of new polysaccharides in the current PCVs, mainly for low- and middle-income countries, and we will also address future perspectives.

Bacteremia-Induced Cholestatic Jaundice as a Major Manifestation of Pneumococcal Infection in a Healthy Toddler

AbstractThe development of pneumococcal conjugate vaccines has substantially decreased the incidence of invasive pneumococcal diseases. However, the incidence of bacteremia due to nonvaccine serotypes has increased. Therefore, it is important to recognize the symptoms and complications of pneumococcal infection to expedite diagnosis. Herein, we report the case of a 22-month-old patient diagnosed with pneumococcal bacteremia who presented with cholestatic jaundice and fever without any other signs of systemic sepsis. The patient's condition improved soon after antibacterial therapy. Other causes of jaundice were possibly ruled out based on the screening test for viral hepatitis, and there were no abnormal findings on abdominal ultrasonography. Therefore, the present case suggests that cholestatic jaundice could be a manifestation of pneumococcal bacteremia.

Resistant Streptococcus pneumoniae strains in children with acute otitis media\u2013 high risk of persistent colonization after treatment

BackgroundDespite advances in the development of pneumococcal conjugate vaccines, acute otitis media (AOM) is a common childhood infection, caused mainly by Streptococcus pneumoniae. It has been suggested that persistence of pneumococcal nasopharyngeal carriage is a risk factor for subsequent recurrent infections.MethodsIn this study we evaluate the relationship between 55 pneumococcal strains obtained from nasopharynx/oropharynx (NP/OP) and middle ear fluid (MEF) of 62 children, aged between 1 and 16 years, during AOM (including recurrent/treatment failure AOM, and post-treatment visits), based on their phenotypic and genotypic characteristics performed by analyses of serotype, antibiotic susceptibility patterns and multilocus sequence typing.ResultsS.pneumoniae was isolated from 27.4% of MEF samples; it constituted 43.6% of all positive bacterial samples from MEF samples. There was statistically significant concordance between isolation from the MEF sample and NP/OP colonization by S. pneumoniae (p < 0.0001). During post-treatment visits S.pneumoniae was isolated from 20.8% of children; 91% of them were positive in pneumococcal NP/OP culture during AOM. The serotypes belonging to 10- and 13-valent pneumococcal conjugated vaccines constituted 84% and 92% of the strains, respectively. Multidrug resistance was found in 84% of the strains. According to multivariate analysis, pneumococcal colonization after antibiotic therapy was significantly associated with shorter length of therapy in children with bilateral AOM.ConclusionsHigh persistent prevalence of antibiotic-resistant S.pneumoniae strains in children with AOM after unsuccessful bacterial eradication may presumably be regarded as a predisposing factor of infection recurrence.

Influenza and pneumococcus vaccination: current recommendations

Acute asthmatic exacerbation and hospital admission may be associated with severe influenza infection. It has been reported that immunization with inactivated influenza vaccine in patients with persistent asthma decreased respiratory illnesses and asthmarelated events. Evidence from more recently published randomized trials indicated that there is no significant increase in asthma exacerbations immediately after influenza vaccination. Similarly, inactivated influenza vaccine in chronic obstructive pulmonary disease (COPD) patients resulted in a significant reduction in the total number of exacerbations when compared with placebo. The highest incidence of invasive pneumococcal disease occurs in children <5 years of age, immunocompromised persons such as HIV, and those ≥65 years of age. Therefore, pneumococcal vaccine has been recommended for all adults ≥65 years of age and in younger patients who have a condition that increases the risk of invasive pneumococcal disease or pneumococcal pneumonia. The development of pneumococcal conjugate vaccines represents a major advance, and the use of such vaccine has reduced the incidence of pneumococcal disease and acute exacerbation in COPD patients. There are limited data about the effect of pneumococcal vaccine on asthmatic patients.

Assessing non-inferiority to an aggregate response with an application to development of pneumococcal conjugate vaccines

The development of a new pneumococcal conjugate vaccine involves assessing the responses of the new serotypes included in the vaccine. The World Health Organization guidance states that the response from each new serotype in the new vaccine should be compared with the aggregate response from the existing vaccine to evaluate non-inferiority. However, no details are provided on how to define and estimate the aggregate response and what methods to use for non-inferiority comparisons. We investigate several methods to estimate the aggregate response based on binary data including simple average, model-based, and lowest response methods. The response of each new serotype is then compared with the estimated aggregate response for non-inferiority. The non-inferiority test p-value and confidence interval are obtained from Miettinen and Nurminen's method, using an effective sample size. The methods are evaluated using simulations and demonstrated with a real clinical trial example.

Pneumococcal serotype matters

The development of pneumococcal conjugate vaccines requires knowledge of specific serotypes causing disease. The implementation and universal use of 7-valent conjugate pneumococcal vaccine in children in the United States in 2000 has taught us that we need to continue to monitor the relative importance as well as the population-based incidence of disease caused by specific serotypes of Streptococcus pneumoniae. Both have shifted in surprising ways in less than a decade of conjugate vaccine use in the United States. Specific serotypes and relevant pneumococcal diseases vary by demography and geography. In this issue of The Journal, Hortal et al provide difficult-to-obtain serotype data on 387 culture-proven cases of pneumococcal pneumonia in Uruguayan children. They show that universal implementation of the 7-valent conjugate pneumococcal vaccination in Uruguay, even if 100% effective, would be expected to prevent only 60% of cases of pneumococcal pneumonia requiring hospitalization. The more we learn, the more we realize that disease due to S. pneumoniae—with at least 90 serotypes and a niche in the normal flora of the respiratory tract—will be far more difficult to prevent using protein-conjugate polysaccharide vaccines than was and still is disease due to Haemophilus influenzae type b.

Development and Evaluation of Pneumococcal Conjugate Vaccines: Clinical Trials and Control Tests

Streptococcus pneumoniae is a major cause of pneumonia, meningitis, and otitis media and is responsible for disease in young children, the elderly, and immunocompromised individuals. Emerging high-level resistance to penicillin, multiple antibiotics, and tolerance to vancomycin emphasizes the importance of preventing pneumococcal infection by alternative methods such as immunization. The development of pneumococcal conjugate vaccines using the same carrier proteins as those used in Hemophilus influenzae type b vaccines has enhanced the immune response in infants and children compared with polysaccharide vaccines and has significantly improved the ability to prevent pneumococcal disease in this population worldwide. Here we review the clinical trials of multivalent pneumococcal conjugate vaccines under evaluation, identify potential carrier proteins considered for development of future pneumococcal conjugate vaccines, discuss issues regarding licensure of new candidate vaccines from a clinical trial and quality control perspective, and alternative vaccine strategies for the prevention of pneumococcal disease.

Proportion of invasive pneumococcal infections in German children preventable by pneumococcal conjugate vaccines.

The incidence and serotype distribution of Streptococcus pneumoniae as a cause of invasive diseases are unknown with regard to most European countries. From January 1997 through December 1998, population-based nationwide prospective surveillance was undertaken for invasive pneumococcal disease (IPD) in children in Germany, based on monthly independent reports from all pediatric hospitals and from clinical microbiology laboratories. On the basis of 896 reported IPD cases (including 404 with meningitis), the incidences per 10(5) children in different age groups were as follows: children aged <1 year, 18.9 (9.7 for meningitis); children aged <2 years, 16. 0 (7.2 for meningitis); for children aged <5 years, 8.9 (3.9 for meningitis); and for children aged <16 years, 3.2 (1.4 for meningitis). The proportions of cases involving strains (304 serotyped) included in conjugate vaccines were as follows: for the 7-valent vaccine, 52%; for the 9-valent, 62%; and for the 11-valent, 71%. None of the isolates were resistant to penicillin or cefotaxime. Although the rate for meningitis is similar, other manifestations of IPD are less commonly diagnosed in Germany than in other countries. The serotype distribution only partially matched that used in the recent development of pneumococcal conjugate vaccines.