Why don't vaccines work in some older adults?

Researchers at the Jackson Laboratory (JAX) and UConn Health are rigorously studying why i vaccines they don't work as well in some older adults. An important aspect of aging is how the immune system changes over time. Such changes have consequences and contribute to increasing the risk of serious infections and other diseases such as cancer in the aging population.

The results of the study were published in Nature Immunology.

Vaccines: Some seniors don't get their benefits

Streptococcus pneumoniae is a dangerous bacterial pathogen that causes diseases such as pneumonia, meningitis and sepsis. Newborns and the elderly are at greatest risk for pneumococcal infections, and mortality rates increase with age for reasons that are not well understood.

Fortunately, several vaccines developed against polysaccharides on the surface of S. pneumoniae, including PPSV23 (Pneumovax), are generally effective in older adults, although not as protective as in younger adults. Combining (conjugating) the polysaccharide with a protein, such as a non-toxic variant of diphtheria toxin, can induce further adaptive immune activation, resulting in better protection.

The strategy has been used to develop a new class of FDA-approved conjugate vaccines (e.g., PCV13, Prevnar). Despite these advances, responses to pneumococcal vaccines continue to decline with age. Furthermore, it is unclear which of these is preferable in subpopulations of older adults.

To fill these gaps in knowledge, a team led by JAX Associate Professor Duygu Ucar, Ph.D., UConn Professor of Health and Director of the UConn Center on Aging George Kuchel, MD, CM, and Jacques Banchereau, Ph.D. (Immunoledge, Montclair, NJ), recruited and vaccinated a cohort of 39 healthy pneumococcal vaccine-naïve adults, all aged 60 years or older, to accurately compare pre- and post-vaccine immune characteristics.

Their findings, presented in “Distinct baseline immune characteristics associated with responses to conjugated and unconjugated pneumococcal polysaccharide vaccines in older adults,” published in Nature Immunology, identify the biological traits underlying the variable responses to the two different vaccines. Importantly, they also reveal distinct baseline (i.e. pre-vaccination) predictors that have the potential to influence vaccination strategies and lead to interventions that are more effective, as they are more specific.

“Understanding who will respond strongly to which vaccine will provide us with the opportunity to stratify the population to improve vaccine efficacy at the population level, as well as understanding whether we can modulate individuals' immune characteristics prior to vaccination to improve outcomes at the population level. individual,” says Ucar.

All participants 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 later to provide longitudinal data. After vaccination, researchers developed measures to quantify vaccine responses and classify donors with respect to responsiveness within the cohort. Although overall responses to both vaccines were comparable, there were clear differences in underlying immune phenotypes, separating strong and weak responders.

The background abundance of two specific types of T cells, Th1 and Th17 cells, played an important role in responses to PCV13. Th1 cells produce molecular signals to activate early innate immune responses to pathogens, while Th17 cells also contribute to the defense response by producing a diverse group of inflammatory signaling molecules.

For PCV13 vaccine responses, higher levels of Th1 cells showed a positive association and higher levels of Th17 cells a negative association. Therefore, the pre-vaccination Th1/Th17 ratio may be predictive of the strength of response to PCV13. Interestingly, women had a higher frequency of Th1 cells and a lower frequency of Th17 cells than men and responded more strongly to the PCV13 vaccine.

From pre-vaccination gene expression data, the researchers discovered a genetic module that included cytotoxic genes associated with reduced responses to PCV13, 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 the blood was associated with responses to PCV13, where weak responders had more CD16+ NK cells than strong responders. However, the CYTOX signature was not associated with responses to the alternative vaccine PPSV23: another distinct gene set predicted responses to PPSV23.

“Our study is a reminder that “one size fits all” approaches do not work well for older patients,” says Kuchel. “Furthermore, if our findings can be replicated in other populations, they could offer significant opportunities to implement models of care for older adults involving precision gerontology that are more effective because they are more precise, ultimately matching individuals to those vaccines that work better for them.”

A striking aspect of the study is that the underlying predictors for the two available classes of pneumococcal vaccines are quite distinct and independent of each other, despite both vaccines using the same bacterial polysaccharides to elicit 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 results imply that individuals can be easily stratified based on which vaccine is likely to work best for them .

For example, older adults with low levels of CYTOX/CD16+ NK cells will likely respond well to the PCV13 vaccine, while those with high CYTOX would more likely benefit from the PPSV23 vaccine.

Overall, the findings have important implications for more precise vaccination strategies for pneumococcal vaccines, and potentially other vaccines as well, to better protect older adults from infection and disease.

Since the introduction of the pneumococcal conjugate vaccines, PCV7 and PCV13, rates of invasive pneumococcal infection (IPD) among children with sickle cell disease (SCD) have decreased significantly. The study explores the effectiveness of existing and emerging vaccines to protect children with SCD from life-threatening infections.

SCD is the most common inherited red blood cell disorder in the United States, affecting approximately 100,000 people. According to the Centers for Disease Control and Prevention (CDC), SCD affects one in 365 births to blacks or African Americans and one in 16,300 births to Hispanic Americans.

Children with SCD typically develop splenic dysfunction within the first six months to one year of life. Th
e spleen plays a vital role in protecting the human body from infections, and children suffering from sudden death are at greater risk of developing serious and life-threatening diseases. Those with this condition are treated with penicillin prophylaxis to reduce the risk of infection-related death.

Before treatment with penicillin, one in ten children under the age of five developed IPD, a serious infection, every year. This accounted for 32% of all causes of death for individuals with sickle cell disease younger than 20 years in the Sickle Cell Cooperative Study. However, as antibiotic resistance has increased in recent decades, researchers have had to turn to new methods, such as vaccines, to protect this vulnerable population.

“In the 2000s, when pneumococci were developing resistance to antibiotics, PCV7/PCV13 conjugate vaccines were introduced,” explained Thomas Adamkiewicz, MD, MSc, a pediatric hematologist at Morehouse School of Medicine. “Because these vaccines were developed to target bacterial serotypes that are currently not covered. We examined the impact of current and potential coverage of the latest vaccinations.”

The researchers analyzed 25 years of data collected by the Georgia Emerging Infections Program, part of the Centers for Disease Control and Prevention's (CDC) Active Bacterial Surveillance Network, which identifies all IPDs occurring in the Georgia metropolitan area. Atlanta since 1994.

Researchers from the Georgia Emerging Infections Program, Children's Health Care of Atlanta and Emory University collaborated on this study. They identified 104 episodes of IPD in 3,707 children younger than 10 years with HbSS and HbSC variants of SCD.

According to the researchers' data, after 2002, 87% of children with SCD received one or more doses of PCV7 or PCV13 vaccines in the first decade of life. Dr. Adamkiewicz and his team found that between 1994-1999 and 2010-2018, rates of IPD fell by 87 percent in children from birth to four years old with HbSS, the most severe form of SCD, and by 80% in those aged between five and four years.

They also identified that among children with HbSS and IPD, mortality rates decreased from 14% to 3% after 2002, and meningitis rates decreased from 16% to 8%. The scientists also observed that penicillin resistance was more prevalent among this population before the approval of the PCV7 vaccine.

After 2000, IPD strains with serotypes not covered by the existing PCV7 and PVC13 vaccines emerged and caused the majority of IPDs. The older 23-valent pneumococcal polysaccharide vaccine (PPSV23) was effective against pneumococcal strains with serotypes other than PCV13, within three years of vaccination.

The researchers identified that since the licensing of PCV7, rates of IPD in children with SCD aged five years and older have decreased significantly. Furthermore, since the approval and introduction of the PCV13 vaccine, no IPD infections related to the PCV13 strain have been recorded, despite some children with SCD not receiving the full recommended vaccination regimen.

These findings suggest that the herd immunity introduced by these vaccines into the general population is helping to protect children with SCD from infection as well.

Dr. Adamkiewicz points out that because bacterial strains with serotypes not covered by the current vaccine are predominant, children with SCD may benefit from receiving recently approved vaccines such as PCV15 and PCV20, which cover 16% and 51%, respectively of IPD strains not covered by PCV13.

“A big question is the role of penicillin prophylaxis in children with SCD receiving new vaccines,” said Dr. Adamkiewicz. “We need a lot more data to make recommendations.”

Data from this study is limited to one region of the United States, but its findings could offer insights into the impact such vaccines would have on individuals with SCD in Africa, where the majority of children with SCD reside.

Although approximately two-thirds of children in the general population have received the PCV13 vaccine, mortality in children with sickle cell disease remains high, suggesting the need for wider dissemination of preventive measures, including vaccines.

In 2020, in light of this need, the ASH Consortium on Newborn Screening in Africa (CONSA) was established, an international network that seeks to demonstrate the benefits of newborn screening and early interventions for children with sickle cell disease in Sub-Saharan Africa.

Although IPD remains a life-threatening risk for children with SCD, this study highlights the need for vaccines targeting broad strains of pneumococcal bacteria and further research to continue to advance prophylactic treatments available for this population.