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Journal: Vaccine

207

There has been enormous debate regarding the possibility of a link between childhood vaccinations and the subsequent development of autism. This has in recent times become a major public health issue with vaccine preventable diseases increasing in the community due to the fear of a ‘link’ between vaccinations and autism. We performed a meta-analysis to summarise available evidence from case-control and cohort studies on this topic (MEDLINE, PubMed, EMBASE, Google Scholar up to April, 2014). Eligible studies assessed the relationship between vaccine administration and the subsequent development of autism or autism spectrum disorders (ASD). Two reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus with another author. Five cohort studies involving 1,256,407 children, and five case-control studies involving 9920 children were included in this analysis. The cohort data revealed no relationship between vaccination and autism (OR: 0.99; 95% CI: 0.92 to 1.06) or ASD (OR: 0.91; 95% CI: 0.68 to 1.20), or MMR (OR: 0.84; 95% CI: 0.70 to 1.01), or thimerosal (OR: 1.00; 95% CI: 0.77 to 1.31), or mercury (Hg) (OR: 1.00; 95% CI: 0.93 to 1.07). Similarly the case-control data found no evidence for increased risk of developing autism or ASD following MMR, Hg, or thimerosal exposure when grouped by condition (OR: 0.90, 95% CI: 0.83 to 0.98; p=0.02) or grouped by exposure type (OR: 0.85, 95% CI: 0.76 to 0.95; p=0.01). Findings of this meta-analysis suggest that vaccinations are not associated with the development of autism or autism spectrum disorder. Furthermore, the components of the vaccines (thimerosal or mercury) or multiple vaccines (MMR) are not associated with the development of autism or autism spectrum disorder.

Concepts: Public health, Epidemiology, Vaccine, Vaccination, Autism, Autism spectrum

199

Older adults are less able to produce a protective antibody response to vaccinations. One factor that contributes to this is immune ageing. Here we examined whether diurnal variations in immune responses might extend to the antibody response to vaccination.

Concepts: Immune system, Antibody, Vaccination, Immunology, Immunity

149

Pneumococcal infection in children is a major public health problem worldwide, including in Japan. The pneumococcal conjugate vaccine 7 (PCV7) was licensed for use in Japan in 2010 followed by PCV13 in 2013. This report includes the results of a nationwide surveillance of invasive pneumococcal disease (IPD) and non-IPD in paediatric patients from January 2012 to December 2014. We collected 343 isolates from 337 IPD patients and 286 isolates from 278 non-IPD patients. Of the IPD isolates, the most identified serotypes included 19A, 24F, and 15A. The prevalence of non-PCV13 serotype isolates increased significantly from 2012 to 2014 (51.6-71.4%, p=0.004). Serotypes 19A, 15A and 35B were highly non-susceptible to penicillin, and the rates of non-susceptible isolates from IPD patients to penicillin and cefotaxime significantly declined during the study period (p=0.029 and p=0.013, respectively). The non-susceptible rate to meropenem increased, particularly for serotype 15A. The IPD isolates comprised clonal complex (CC) 3111 (93.8% was serotype 19A) followed by CC2572 (81.5% was serotype 24F) and CC63 (97.1% was serotype 15A). CC3111, CC63 and CC156 (33.3% was serotype 23A, 28.6% was serotype 6B, and 14.3% was serotype 19A) were highly non-susceptible to penicillin. Of the non-IPD isolates, the most identified serotypes included 19A, 15A, and 3. In conclusion, the introduction of PCV7 and PCV13 resulted in increasing non-PCV13 serotypes and clones, including antimicrobial resistant serotypes 15A and CC63 (Sweden(15A)-25 clone).

Concepts: Microbiology, Pneumonia, Streptococcus pneumoniae, Streptococcus, Pneumococcal infection, Pneumococcal conjugate vaccine, Pneumococcal vaccine, Pneumococcal polysaccharide vaccine

143

Vaccine exposure to temperatures below recommended ranges in the cold chain may decrease vaccine potency of freeze-sensitive vaccines leading to a loss of vaccine investments and potentially places children at risk of contracting vaccine preventable illnesses. This literature review is an update to one previously published in 2007 (Matthias et al., 2007), analyzing the prevalence of vaccine exposure to temperatures below recommendations throughout various segments of the cold chain. Overall, 45 studies included in this review assess temperature monitoring, of which 29 specifically assess ‘too cold’ temperatures. The storage segments alone were evaluated in 41 articles, 15 articles examined the transport segment and 4 studied outreach sessions. The sample size of the studies varied, ranging from one to 103 shipments and from three to 440 storage units. Among reviewed articles, the percentage of vaccine exposure to temperatures below recommended ranges during storage was 33% in wealthier countries and 37.1% in lower income countries. Vaccine exposure to temperatures below recommended ranges occurred during shipments in 38% of studies from higher income countries and 19.3% in lower income countries. This review highlights continuing issues of vaccine exposure to temperatures below recommended ranges during various segments of the cold chain. Studies monitoring the number of events vaccines are exposed to ‘too cold’ temperatures as well as the duration of these events are needed. Many reviewed studies emphasize the lack of knowledge of health workers regarding freeze damage of vaccines and how this has an effect on temperature monitoring. It is important to address this issue by educating vaccinators and cold chain staff to improve temperature maintenance and supply chain management, which will facilitate the distribution of potent vaccines to children.

Concepts: Vaccine, Temperature, Influenza, Segment, Cold, Logistics, Supply chain management, Supply chain

140

Over the past decade, several countries across all regions, income groups and procurement methods have been unable to secure sufficient BCG vaccine supply. While the frequency of stock-outs has remained rather stable, duration increased in 2014-2015 due to manufacturing issues and attracted the attention of national, regional and global immunization stakeholders. This prompted an in-depth analysis of supply and demand dynamics aiming to characterize supply risks. This analysis is unique as it provides a global picture, where previous analyses have focused on a portion of the market procuring through UN entities. Through literature review, supplier interviews, appraisal of shortages, stock-outs and historical procurement data, and through demand forecasting, this analysis shows an important increase in global capacity in 2017: supply is sufficient to meet forecasted BCG vaccine demand and possibly buffer market shocks. Nevertheless, risks remain mainly due to supply concentration and limited investment in production process improvements, as well as inflexibility in demand. Identification of these market risks will allow implementation of risk-mitigating interventions in three areas: (1) enhancing information sharing between major global health actors, countries and suppliers, (2) identifying interests and incentives to expand product registration and investment in the BCG manufacturing process, and (3) working with countries for tighter vaccine management.

Concepts: Supply and demand, Consumer theory, Microeconomics, Market, Market economy, Economic surplus, Inverse demand function, Islamic economics in the world

139

Immunization with pneumococcal vaccines is an important prophylactic strategy for children with asplenia or splenic dysfunction, who are at high risk of bacterial infections (including S. pneumoniae). This study aimed to assess immunogenicity and safety of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, GSK) in this at-risk population.

Concepts: Immune system, Microbiology, Pneumonia, Streptococcus pneumoniae, Pneumococcal conjugate vaccine, Otitis media, Haemophilus influenzae, Polysaccharide encapsulated bacteria

138

In 2015, foot-and-mouth disease (FMD) viruses of the A/ASIA/G-VII lineage emerged from the Indian sub-continent to cause outbreaks in the Middle and Near East. A factor which has been proposed to have contributed to the rapid spread of this lineage is the poor in vitro vaccine-match of field isolates to vaccine strains that are commonly used in the region. This study used data from outbreaks on four large-scale dairy farms using routine vaccination in Saudi Arabia, to evaluate the impact of vaccination and learn how to manage outbreaks more effectively in this setting. This evaluation also included an assessment of vaccine-induced neutralisation titres to the vaccine and field strains on a related farm with no history of FMD that employed an identical vaccination schedule. The incidence risk among exposed groups ranged from 2.6 to 20.1% and was significantly higher among youngstock (18.7%) compared to adults (7.4%). Evidence was found that local isolation of individual sick animals was more effective than whole group isolation and that subclinical infection and undetected circulation may occur on large-scale farms in Saudi Arabia, although both of these points require further evaluation. On the unaffected farm, the mean reciprocal titres for the vaccine and field strains were all above the cut-off supposed to correlate with clinical protection based on evidence from challenge studies. An estimate of vaccination effectiveness was not possible on the affected farms, but the incidence of FMD provides a more realistic estimation of the expected vaccine performance than in vivo studies or r1 value as it is based on field conditions and natural exposure. This study shows that analysis of field data from FMD outbreaks are a useful addition to more conventional challenge and in vitro based evaluations of vaccines and suggests further work is necessary to validate correlates of protection in field conditions.

Concepts: Vaccine, Vaccination, In vivo, Vaccination schedule, Saudi Arabia, Middle East, Aphthovirus, Foot-and-mouth disease

136

The divergence of regulatory requirements and processes in developing and emerging countries contributes to hamper vaccines' registration, and therefore delay access to high-quality, safe and efficacious vaccines for their respective populations. This report focuses on providing insights on the heterogeneity of registration requirements in terms of numbering structure and overall content of dossiers for marketing authorisation applications for vaccines in different areas of the world. While it also illustrates the divergence of regulatory processes in general, as well as the need to avoid redundant reviews, it does not claim to provide a comprehensive view of all processes nor existing facilitating mechanisms, nor is it intended to touch upon the differences in assessments made by different regulatory authorities. This report describes the work analysed by regulatory experts from vaccine manufacturing companies during a meeting held in Geneva in May 2017, in identifying and quantifying differences in the requirements for vaccine registration in three aspects for comparison: the dossier numbering structure and contents, the application forms, and the evaluation procedures, in different countries and regions. The Module 1 of the Common Technical Document (CTD) of 10 countries were compared. Modules 2-5 of the CTDs of two regions and three countries were compared to the CTD of the US FDA. The application forms of eight countries were compared and the registration procedures of 134 importing countries were compared as well. The analysis indicates a high degree of divergence in numbering structure and content requirements. Possible interventions that would lead to significant improvements in registration efficiency include alignment in CTD numbering structure, a standardised model-application form, and better convergence of evaluation procedures.

136

Gastric adenocarcinoma is globally the third leading cause of death due to malignancy, with the bulk of this disease burden being suffered by low and middle income countries (LMIC), especially in Asia. The majority of these cancers develop as a result of a chronic gastritis that arises in response to infection with the stomach-dwelling bacterium, Helicobacter pylori. A vaccine against this pathogen would therefore be a powerful tool for preventing gastric adenocarcinoma. However, notwithstanding a proof-of-concept that vaccination can protect children from acquisition of H. pylori infection, there are currently no advanced vaccine candidates with only a single vaccine in Phase I clinical trial. Further, the development of a vaccine against H. pylori is not a current strategic priority of major pharmaceutical companies despite the large global disease burden. Given the involvement of such companies is likely to be critical for late stage development, there is therefore a need for an increased appreciation of the burden of this disease in LMIC and more investment to reinvigorate research in H. pylori vaccine Research and Development.

Concepts: Immune system, Cancer, Bacteria, Stomach, Helicobacter pylori, Helicobacter, Gastritis

118

Streptococcus pyogenes is an important global pathogen, causing considerable morbidity and mortality, especially in low and middle income countries where rheumatic heart disease and invasive infections are common. There is a number of promising vaccine candidates, most notably those based on the M protein, the key virulence factor for the bacterium. Vaccines against Streptococcus pyogenes are considered as impeded vaccines because of a number of crucial barriers to development. Considerable effort is needed by key players to bring current vaccine candidates through phase III clinical trials and there is a clear need to develop a roadmap for future development of current and new candidates.

Concepts: Immune system, Clinical trial, Bacteria, Microbiology, Vaccination, Streptococcus pyogenes, Rheumatic fever, Streptococcus