Tag: S. pneumoniae

Why Vaccines don’t Work as Well for Some Older People

Photo by Mufid Majnun on Unsplash

Age-related changes in the immune system also play a role in variable responses to vaccines and overall lower efficacy of vaccines compared to younger adults. Researchers at The Jackson Laboratory (JAX) and UConn Health are investigating why vaccines don’t work as well in some older adults, and have published their insights in Nature.

Protection against pneumococcal infections

Infants and older adults are at greatest risk for pneumococcal infections, and case-fatality rates increase with age for reasons still not well understood. Fortunately, several vaccines developed against the polysaccharides found on the surface of Streptococcus pneumoniae, including PPSV23 (Pneumovax), are generally effective in older adults, though less in younger adults. Conjugating the polysaccharide with a protein, such as a nontoxic variant of a diphtheria toxin, can induce additional adaptive immune activation, resulting in better protection. The strategy was used to develop a new class of FDA-approved conjugated vaccines (eg, PCV13, Prevnar). Despite these advances, responses to pneumococcal vaccines still decline with age. Moreover, it remains unclear which of these two vaccines are preferable in subpopulations of older adults.

To address these gaps in knowledge, a team led by JAX Associate Professor Duygu Ucar, PhD, UConn Health Professor George Kuchel, MD, CM, and Jacques Banchereau, PhD (Immunoledge, Montclair, NJ), compared pre- and post-vaccine immune characteristics. Their findings identify the biological traits underlying variable responses to the two different vaccines. Importantly, they also reveal distinct baseline (ie, pre-vaccination) predictors that have the potential to affect vaccination strategies and lead to interventions that are more effective, by virtue of being more specific.

Efficacy indicators

A cohort of 39 pneumococcal vaccine-naïve healthy adults, all aged 60 or above, received a single dose of PPSV23 or PCV13 from May to early fall. Blood was drawn before vaccination, then one, 10, 28 and 60 days after to provide longitudinal data. Following vaccination, the researchers developed measures to quantify vaccine responses and rank donors with respect to responsiveness within the cohort. While overall responses to both vaccines were comparable, there were clear differences in baseline immune phenotypes, separating the strong and weak responders.

The baseline abundance of two specific T cell types, Th1 and Th17 cells, played an important role in PCV13 responses. Th1 cells produce molecular signals to activate early innate immune responses to pathogens, while Th17 cells also contribute to the defence response by producing a different group of inflammatory signalling molecules. For PCV13 vaccine responses, higher levels of Th1 cells showed a positive association and higher levels of Th17 cells a negative association. Thus, a pre-vaccination Th1/ Th17 ratio can be predictive of PCV13 response strength. Interestingly, women have a higher frequency of Th1 and lower frequency of Th1 7 cells compared to men and responded more strongly to the PCV13 vaccine.

From the pre-vaccination gene expression data, the researchers uncovered a gene module that included cytotoxic genes that was associated with reduced PCV13 responses, called the CYTOX signature. Single cell profiling linked this gene expression signature to mature CD16+ Natural Killer (NK) cells. The abundance of mature CD16+ NK cells in blood was associated with responses to PCV13, where weak responders had more CD16+ NK cells than strong responders. The CYTOX signature was not associated with responses to the alternative PPSV23 vaccine, however – another, distinct gene set predicted responses to PPSV23.

“Our study offers a reminder that ‘one size fits all’ approaches do not work well for older patients,” says Kuchel. “Moreover, if our findings can be replicated in other populations, they may offer remarkable opportunities for implementing care models for older adults involving Precision Gerontology that are more effective by virtue of being more precise, ultimately matching individuals with those vaccines that work best for them. Precision Gerontology represents the thematic focus of the UConn Older Americans Independence ‘Pepper’ Center award from NIH.”

Implications for disease prevention

A surprising aspect of the study is that the baseline predictors for the two available classes of pneumococcal vaccines are quite distinct and independent from each other, despite both vaccines using the same bacterial polysaccharides to provoke the protective immune response. Importantly, however, the paper shows that responses to the two vaccines can be predicted in older adults based on specific pre-vaccination characteristics, and the findings imply that individuals can be readily stratified based on which vaccine is likely to work best for them. For example, older adults with low CYTOX/CD16+ NK cell levels will likely respond well to the PCV13 vaccine, while those with high CYTOX would more likely benefit from the PPSV23 vaccine. Overall, the results have important implications for more precise vaccination strategies for pneumococcal vaccines, and potentially for other vaccines as well, to better protect older adults from infection and disease.

Source: University of Connecticut

Indoor Air Pollution Linked to Pneumonia in Children

Streptococcus pneumoniae. Credit: CDC

A new study published in The Lancet Global Health, highlights the impact indoor air pollution can have on the development of child pneumonia, showing that increases in airborne particulate matter results in greater carriage of Streptococcus pneumoniae.

Streptococcus pneumoniae is a major human pathogen causing more than two million deaths per year; more than HIV/AIDS, measles and malaria combined, but it is also part of the normal microbial community of the nasopharynx. It is the leading cause of death due to infectious disease in children under five years of age; in sub-Saharan Africa, the burden of pneumococcal carriage and pneumonia is especially high.

Household air pollution from solid fuels increases the risk of childhood pneumonia. Nasopharyngeal carriage of S. pneumoniae is a necessary step in the development of pneumococcal pneumonia. More than 2.6 billion people are exposed to household air pollution worldwide. Inefficient indoor biomass burning is estimated to cause 3.8 million premature deaths annually and approximately 45% of all pneumonia deaths in children aged younger than five years. However, a causal pathway between household air pollution and pneumonia had not yet been identified.

In order to understand the connection between exposure to household air pollution and the risk of childhood pneumonia researchers from the UK, Malawi and the United States conducted the MSCAPE (Malawi Streptococcus pneumoniae Carriage and Air Pollution Exposure) study embedded in the ongoing CAPS (Child And Pneumonia Study) trial. The MSCAPE study assessed the impact of PM2.5, the single most important health-damaging pollutant in household air pollution, on the prevalence of pneumococcal carriage in a large sample of 485 Malawian children.

Through exposure-response analysis, a statistically significant 10% increase in risk of S. pneumoniae carriage in children was observed for a unit increase (deciles) of exposure to PM2.5 (ranging from 3.9 μg/m³ to 617.0 μg/m³).

Dr. Mukesh Dherani, the study principal investigator, indicated: “This study provides us with greater insight into the impact household air pollution can have on the development of child pneumonia. These findings provide important new evidence of intermediary steps in the causal pathway of household air pollution exposure to pneumonia and provide a platform for future mechanistic studies.”

Study author Professor Dan Pope said: “Moving forward further studies, particularly new randomized controlled trials comparing clean fuels (e.g. liquefied petroleum gas) with biomass fuels, with detailed measurements of PM2.5 exposure, and studies of mechanisms underlying increased pneumococcal carriage, are required to strengthen causal evidence for this component of the pathway from household air pollution exposure to ALRI in children.”

Professor Nigel Bruce, co-principal investigator, stated: “This study provides further important evidence that emphasises the need to accelerate to cleaner fuels, such as LPG, which are now being promoted by many governments across the continent in order to meet SDG7 by 2030.”

Source: University of Liverpool

AMR Caused Over 1.2 Million Deaths Globally in 2019

Methicillin-resistant Staphylococcus aureus (MRSA) bacteria. Credit: CDC

Globally, infections by antimicrobial-resistant (AMR) bacteria caused more than 1.2 million deaths worldwide in 2019, according to a study published in The Lancet. It is the largest and most comprehensive one to date of this critical issue.

Lower-income countries are worst affected but antimicrobial resistance remains a global threat, the researchers wrote.

The researchers emphasised that investment in new drugs is urgently needed, as well as vaccination and better antimicrobial stewardship.

The estimate of global deaths from AMR, is based on the researchers’ analysis of 204 countries, assuming the counterfactual that the bacteria responsible would be antibiotic-susceptible.

Of the 4.95 million deaths in which AMR played a role, 1.27 million were directly attributable to it. In 2019, 860 000 deaths were estimated from HIV and 640 000 from malaria.

Most of the AMR-related deaths resulted from lower respiratory infections, such as pneumonia, and bloodstream infections, which can lead to sepsis.

Deaths from AMR were estimated to be highest in sub-Saharan Africa at 23.7 deaths per 100 000, and lowest in North Africa and the Middle East at 11.2 per 100 000. Young children are at most risk, with about one in five deaths linked to AMR being among the under-fives.

The researchers also noted that “resistance is high for multiple classes of essential agents, including beta-lactams and fluoroquinolones.”

MRSA (methicillin-resistant Staphylococcus aureus) was particularly deadly, while E. coli, K. pneumoniae, S. pneumoniae, A. baumannii, and P. aeruginosa were associated with high levels of resistance. The researchers wrote that “each of these leading pathogens is a major global health threat that warrants more attention, funding, capacity building, research and development, and pathogen-specific priority setting from the broader global health community.”

They also recommend that immunity to these pathogens be built up by vaccination, and since currently only S. pneumoniae has a vaccine readily available, these will need to be developed and deployed as a matter of urgency. They noted several limitations to their study, the first being the sparsity of data drawn from low- and middle-income countries, which may in fact lead to an underestimate of the prevalence of AMR. Secondly, there is the possibility of multiple sources of bias inherent in combining datasets from different providers. Finally, there may be bias in surveillance, eg if cultures are drawn only if a patient is unresponsive to antibiotics, leading to an overestimate.

Source: The Lancet