The session had various presentations on serotype epidemiology of residual pneumococcal disease in adults, pneumococcal pneumonia in older adults, adult pneumococcal vaccination programs and optimizing prevention of adult pneumococcal disease in the era of higher valency vaccines.

The first presentation by Dr. Mark van der Linden epidemiology of the residual pneumococcal disease in adults and the importance of having time surveillance. Pneumococcal disease normally affects the nasopharynx and remains asymptomatic; but, when they travel to other parts they can cause otitis media, sinusitis and non-invasive bacteremia or pneumonia. When the pneumococci enter the bloodstream they cause invasive pneumococcal disease, bacteremia and pneumonia and in very severe cases they can cause sepsis or meningitis. Pneumococcal disease appears at the extremes of age with highest incidence in very young children and in the elderly. The presentation of pneumococcal disease is different among children and adults. In children, it is mainly otitis media followed by pneumonia, severe bacteremia, sepsis and meningitis. In adults, the main presentation is pneumonia, of which 25% is bacteremic pneumonia followed by sepsis and meningitis. Data from Germany has demonstrated that the highest number of cases are among children and older adults, but the children < 2 years only make up 3.4% of invasive pneumococcal disease (IPD) while 67% of IPD is in adults. With respect to pneumococcal vaccines, the first whole cell vaccines were in South Africa in 1911 after which polysaccharide vaccines were discovered. The conjugate vaccines which were formed later had a drastic impact on the epidemiology. At present there are 15- and 20-valent conjugate vaccines available. There is a vaccine in development by MSD, which is V116 aimed to be used in adults. Another vaccine in development is the 24 valent AFX3772 with new conjugate technology by GSK. Administering childhood pneumococcal conjugate vaccination for IPD in children helps in producing herd protection towards adults. In adults, there is an increasing amount of disease burden despite vaccination. There are certain serotypes such as PCV 03 and 19A and 19F which do not react to herd protections. Vaccinations (especially the newer vaccines) help to lower the burden of serotypes that cause IPD among adults. The type 13 serotypes affect basically 13 serotypes and there are new non-PCV serotypes which are AFX3772 and V116. The top 20 serotypes which are not PCV are for the larger part conferred coverage by new vaccines and future vaccines. The percentage of the coverage of the non-PCV serotypes covered- PCV15 is 11-12%, PCV20 is 44-51%, PCV 24 is 55-59% and V116 is 78-88%. In adults > 60 years, the coverage of vaccines V116 is 85.5%. The complementary strategy is based on having PCV7 serotype suppressed in children. In Denmark, the current formulations have a low coverage. In Germany during the COVID-19 pandemic, there was an increase in the cumulative number of cases of IPD in adults during winter. After the end of the pandemic, there was an enormous increase in the number of reported cases of IPD. From 1992-2023, there were temporal secular trends with serotype 12 where it completely disappeared at the start of the pandemic. The set of cases from December 2022 to February 2023 have a peculiar trend where there are up to 47% PCV13 serotypes as opposed to 30% in December 2019-20. This is alarming because PCV13 serotype disease goes at the cost of the increment of coverage with PCV15 and PCV20. Low levels of vaccination and post-pandemics could be the probable reason for the rise in these numbers. In conclusion, pneumococcal vaccination has had a strong effect on serum distribution of pneumococcal disease. Vaccine serotypes have decreased both among directly vaccinated children and among adults to herd protection; however, herd protection seems to be limited. Non-PCV types are gaining importance in IPD adults with serotypes 8, 22F, 9N and11A playing an important role in the three European countries. Newly available and future vaccines can considerably add to the serotype coverage.

The next presentation by Dr. Kelly Johnson discussed the interim results of the PNEUMO study on pneumococcal pneumonia in older adults. The burden of pneumococcal disease remains high and the burden of non-bacteremic pneumococcal pneumonia (NBPP) is far greater than the burden of IPD. There is a lack of population-based surveillance and an easy way of detecting NBPP. There is a limited value of commercially available diagnostic tests for pneumococcal pneumonia and there is a lack of routine diagnostic methods of identification of vaccine serotypes which are associated with pneumococcal pneumonia. The PNEUMO study was a multi-country, prospective, population-based surveillance study whose main objective is to estimate the pneumococcal pneumonia incidence. It included the adult population who were hospitalized with community acquired pneumonia (CAP). It also included a longitudinal evaluation of mental outcomes, such as functional status, cognitive status, quality of life as well as costs. The study procedures included urine collection to test against BinaxNow, a urinary antigen testing detection assay for Streptococcus pneumoniae. The study recorded results of bacterial cultures, including the blood cultures, and recorded results for COVID 19 testing. Some of the assessments included the delirium assessment, confusion assessment, home living status, activation of daily living, cognition, quality of life and employment. The results presented in this session were from the USA (n=2694); 174 patients tested positive for CAP and 30 patients had IPD. There was an increase in the incidence of pneumococcal pneumonia in September 2018-August 2019 which was 43/100,000 per year. It decreased to 27/100,000 per year in September 2019-August 2020 and 9 /100,000 per year in November 2020-October 2021. As of January2023 the results for 50 patients reported the following main serotypes-3, 23A, 35B, 9 and 20. With respect to the quality of life, the higher scores for misery indicated a lower quality of life. For both pneumococcal and non-pneumococcal patients, the EQ-5D-5L Misery scores increased at enrolment (from baseline of 2 weeks prior to hospitalisation) and decreased 6-months later but did not completely return to baseline. Cognitive assessment showed that 58% of pneumococcal and 52% of non- pneumococcal pneumonia cases or patients had a M-CA-Blind score < 18 suggestive of cognitive impairment. In the PNEUMO-EU (European section) study, 3197 patients with CAP were enrolled among which 65 had IPD. The mortality in the overall group as compared to the pneumococcal was about 2.5%. There were more ICU admissions in the pneumococcal group at 11% compared to 7.7% in the overall group. The length of hospital stay was slightly higher at 7 days for the pneumococcal group compared to six for the overall. In this population, serotype 8 dominated followed by serotypes 9, 12 and 34. In summary, the study demonstrated that pneumococcal pneumonia burden persists even after COVID 19 pandemic and it is important to do additional surveillance to monitor the pneumococcal pneumonia burden.

The session discussed the success story of implementation of a vaccine program during a pandemic in Denmark. A bill was passed by the Danish Parliament on 2nd April 2020 to allocate funds to increase flu vaccine coverage and to immunize adults for pneumococcal disease. PPV23 was chosen because PPV20 vaccine covered PCV13 serotypes and non-PCV serotypes. A meta-analysis has shown that using PPV 23 would protect against invasive disease, most likely against pneumococcal pneumonia. After the bill was passed, the focus was on immunizing elderly people in nursing care facilities who are at high-risk and other high risk groups. After June 2020, it was free for all > 65 or older. In Denmark, the general practitioners in the country provide childhood vaccination; 90% of all flu vaccines are given by GP to elderly. Denmark is a highly digitized country and everyone has a personal identification number that links everything together. The success of vaccination in Denmark has several reasons. A large majority of the population (96%) receive digital mail from any public institution. All vaccines provided by the public (> 99%)and private vendors were reported to the Danish vaccine register and the prescriptions were captured by the Danish prescription register. Reminders were sent to the people to visit their physicians to receive immunization. A Danish cohort looking at the effectiveness of the 23-valent pneumococcal polysaccharide vaccine against IPD showed an overall effectiveness of 42% in the model adjusted for age and sex. When serotypes were included in the vaccine, the vaccine effectiveness increased to 58%. In conclusion, of the 1 million eligible for vaccination, 77% were immunized. The vaccine program was a success because it was free of cost, there was an existing infrastructure, increased digitization, high level of public trust in government and high belief in science.

Serotype replacement does not begin in disease, but actually in the carriage of the disease. The infant nasopharynx is the location where the biology, the ecology, the transmission of the pneumococcus happens. It can be asymptomatic and still spread throughout the infant population. When a PCV program is introduced, the post-vaccine carriage rate in infants is very similar to that before the vaccine. So, there is a 100% serotype replacement in the carriage. The effects of the vaccine are impacted as the invasiveness of the pneumococcus changes. The mean invasiveness determines your burden of invasive disease. When we disrupt that population with vaccines, invasiveness changes because the composition of that current population is altered. When invasiveness decreases there is a net benefit from vaccination. Pneumococcal prevalence is not determined primarily by transmission but due to competition. A study sequencing very high carriage of the pneumococcal diversity from an individual nasal pharynx revealed higher levels of multiple colonization than you do with even the most sensitive stereotyping methods. The second and third serotypes are more difficult to detect because many of them are suppressed at very low frequencies. The disease can be minimised by reducing the invasiveness of the post-vaccine population. PCVs can achieve this by direct protection or by elimination of the invasive types and replacing them with less invasive types. This can give a population-wide herd protection. As the valence of infant PCV expands, there is a decreasing invasiveness differential where the benefit of replacing an invasive serotype with a less invasive serotype is limited by population structure. Data from meta-analysis of case carrier studies theoretically demonstrates that the most effective PCV is when you can replace the most invasive serotypes with the least invasive ones on the right. When there are diminishing returns, only less invasive types can be added because there are a limited number of common, highly invasive serotypes in pneumococcal species. If they are replaced with those having similar invasiveness, then net benefit needed to reduce your burden of pneumococcal disease is not achieved. The invasiveness is not entirely the same in children and in adults and perfect serotype replacement in children may not be as optimal in adults. There is diversification in the serotypes that are causing disease in different countries. There is a large diversity of serotypes of causing disease which is a challenge if we want to develop a single universal formulation that targets all this disease and across different countries. An optimal vaccine formulation can be developed starting with the genomic epidemiology of the species. A based on the principles of negative frequency dependent selection recapitulates what we observe in the genomic data and shows that vaccine types are being eliminated over time and replaced by different non vaccine types. The vaccine optimization criteria include disease in children, population-wide impact of the vaccine, difficult to treat diseases and time-point for the population to reach equilibrium. The Bayesian optimization algorithm shows that the best performing vaccines are the 20-valent and the 15-valent vaccines and they outperform the 10-valent vaccines. Children receive carriage- blocking BCG vaccines which lead to population-wide herd immunity; but there is limited benefit from direct protection. Whereas if you give an adult specific vaccine, they can also benefit from direct protection as well as receive herd protection from the infants. There is a high risk of serotypes being eliminated from carriage because they could easily be replaced by more invasive types; but direct protection can be given against it which can have a large positive effect. The addition of 10 extra serotypes to an existent 10-valent vaccine does not have the same benefit. If a complementary vaccine with high efficacy is used, there can be a substantial decrease in IPD. Infant vaccines should target serotypes that are highly invasive while adult vaccines should target ones that are either invasive or just very prevalent in carriage. In conclusion, diversity of lower valency vaccines may be better than a single higher valency vaccine and designing complementary pair or child and adult vaccines would optimally deploy vaccine antigens to limit overall pneumococcal disease.

European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2023, 15-18 April 2023, Copenhagen, Denmark