The session discussed the pneumococcal disease, efficacy of pneumococcal conjugatevaccine (PCV), the next-generation PCVs and the impact of vaccines on Respiratory Syncytial Virus (RSV) Infection.

Next Generation PCV for Protection of Infants by Dr, Keith P. Klugman

The first session the PCV efficacy and the newer PCVs. There is a rapid decline in pneumonia mortality in children over the last 20 years. However, in elderly there is a logarithmic increase with increasing age for pneumonia mortality and COVID-19 has exacerbated that. Pneumococcus is the leading vaccine preventable cause of mortality. After the introduction of the vaccine in the United States (US), there was a remarkable reduction in the PCV7 serotype with a similar trend in adults > 65 years and children. There was a 92% reduction in the year 2007 and close to 100% in the following years. By vaccinating children, adults are protected by herd protection, by interrupting transmission of the disease. Serotype 1 is a major problem in developing countries. Studies from South Africa have shown that serotype 1 disappeared from the region by means of the two plus one vaccine strategy which gave herd protection against serotype 1. Data from the US showed a lowering in the number of invasive pneumococcal disease cases after the introduction of PCV13 However, PCV13 did not have any impact on invasive pneumococcal disease in adults. Serotype 19F reached its lowest point shortly after the introduction of PCV13. With regards to an optimal program, data from Australia shows that the efficacy of the vaccine is seen after 3 doses; in Australia only three doses are given up to six months of age. The three dose strategy is widely used in many poor countries. There is a limited duration of effectiveness against invasive disease, and giving a booster dose is a question of debate. The immunogenicity results from PCV 1+1 study, where the immunogenicity after the booster dose was observed, it was found that geometric mean concentrations (GMCs) against serotype one were better than the two plus one. It was remarkable in an area where serotype 1 was dominant and the protection was maintained with a 1+1 program. However, for serotype 6B, more doses such as 2+1 are better at offering immunogenicity after the booster than other 2 dose strategies. For serotype 19F, 1+1 strategy is effective. The data from Ho Chi Minh City where the control group did not receive a vaccine and the study group received 1+1 strategy showed a significant impact on carriage. Another cluster randomized trial from Vietnam showed that the control cluster which received no pneumococcal conjugate vaccine had 12.8% serotype specific carriage. However, all strategies (0+1, 1+1, 3+0) all greatly reduced carriage. There are several new vaccines introduced in the market for pneumococcus. The Merck 15 valent vaccine, an adult only vaccine, is similar to PCV13 but has added 22F and 33F. The immunogenicity of the Merck 15 valent vaccine is superior to the PCV13, but has low GMCs. The PCV13 is more immunogenic against serotype 6A. The 2 new serotypes in the Merck 15 valent are much more immunogenic as they are not present in the PCV13. The PCV20 which has received an approval from the FDA will be the first 3rd generation 20 plus vaccine to be licensed for use in children. The PCV20 is a new-generation pneumococcal vaccine in children which may have a considerable public health impact. The licensure for this vaccine was based on some different criteria than what have been used in the past. There were two co-primary endpoints. The first was the non-inferiority of the GMC's after the toddler dose. The second was the percentage of participants with IgG above the pre-defined levels of 0.35. It was observed that non-inferiority was met for 14 of 20 serotypes. For the end point of GMC after the infant series, non-inferiority was met by two PCV20. PCV13 was more immunogenic than PCV20 and PCV20 elicited lower GMCs for all PCV13 serotypes and 12F. With respect to the non-inferiority of IgG GMCs after toddler

dose, all 20 vaccine serotypes met non-inferiority. PCV20 was designed to cover the additional seven serotypes that cause disease in adults in the United States. PCV24 is a similar vaccine based on the pneumococcal polysaccharide 23 serotypes plus serotype 6A. It is not strictly a conjugate vaccine and there is no infant data. The PCV25 INVENTPRISE contains 26 serotypes and is designed for the serotypes that cause invasive disease in children in developing countries. Serotype 2 occurs only in a few countries but has been found in children. It has epidemic potential. Serotype 15A is an important antibiotic resistance serotype in children not present in the current 20 valent vaccine. The 24F 24 is a major strain in Europe causing multi-resistant invasive disease. The coverage can be expanded by directing vaccines against pediatric serotypes and adding other 5 serotypes. In conclusion, despite deaths declining in children, pneumonia remains a major killer in both children and adults. PCVs rolled out in many low- and middle-income countries with reduced mortality; however, there is residual disease due to serotypes 3 and 19F. Herd protection is extraordinary across all ages, and a booster dose plays a useful role. Innovation in dosing schedules may give similar effectiveness, but its use must be expanded to make it cheaper for poor countries.

Prevention of RSV: The Next Frontier to Reducing Childhood Pneumonia by Dr. Shabir A, Madhi

The second session discussed the prevention of Respiratory Syncytial Virus (RSV) Infection. A European study conducted across five countries shows that in the first 12 months of life, about 25% of all children have a respiratory illness due to RSV, about 14% among these have a medically-attended illness; 2% of these are hospitalized and 0.1% are ventilated. In high income countries, the data on the contribution of RSV to death is lacking. The Child Mortality Prevention Surveillance Program (CHAMPS) conducts postmortem sampling of multiple tissues to get an objective measure towards the cause of death. In CHAMPS, one of the striking findings regarding death in children from pneumonia was that 75% of children had two or more organisms. Overall, gram negative bacteria were the most common causes of death in children in low- and middle-income countries. The reason for this is that gram negative bacteria are not a part of the empiric treatment. Gram positive cocci are responsible for about 40% infections and remain a high residual burden of pneumococcus. Fifty percent of deaths in children in low middle income countries is due to the pneumococcus and 70% of those and non-vaccine serotypes. With regards to viruses, RSV accounts for 6% of the deaths in children < 5 years. In children between 1-6 months of age, RSV is irresponsible for causing 10% of deaths and pneumococcus accounts for 20% deaths. There is a need for RSV vaccines, as each year there are about 3 million episodes of lower respiratory illness in children; about 10% require hospitalization, about 100,000 children die each year of which 97% occurs in low- and middle-income countries. The first RSV vaccine which was evaluated was the RSV-F nanoparticle RSV protein based vaccine- Novavax. In its clinical trial, the study did not meet the primary end point where the lower bound of the 95% confidence interval for medically significant lower respiratory tract infections (LRTI) should have been greater than 20%. The expanded data analysis showed a 40% reduction in medically significant LRTI, a 40% reduction in LRTI due to hospitalization, and a 60% reduction at the lower bound of the confidence interval at 32% of severe hypoxemia associated with RSV. This study also showed that for all-cause LRTI with severe hypoxemia there was a 47% reduction in the disease irrespective of the etiology. The post-hoc analysis of the vaccine efficacy in South Africa compared to the overall data showed a 56% reduction in medically significant RSV LRTI and 74% reduction in severe RSV LRTI. For the Novavax study and to understand the reductions in hospitalization, the number needed to vaccinate was 50 mothers to prevent one case of medically significant LRTI in babies. However, it was not an immunogenic vaccine and the neutralizing antibodies in the babies were 2.4 to 2.7 times higher in the cord blood of babies born to mothers that received the RSV vaccine. In the RSV vaccine, there is perfusion protein which is a type of antigen exposure that induces much more potent antibody responses. Prefusion F protein induces much stronger neutralizing antibody responses compared to the 2.3 to 2.7 fold increase in cord blood of babies whose mother received the vaccine. In the phase III trial RSV pre-F vaccine in pregnant women and Nirsevimab in infants, the attack rate and RSV hospitalization in the Pfizer placebo group infants was lower (about half) as compared to Nirsevimab. For severe RSV, the attack rate in the placebo group was similar. The lower incidence in the Pfizer group was because Pfizer conducted the study largely during the course of the COVID pandemic. Nirsevimab initially enrolled prior to the onset of the pandemic and they also subsequently enrolled late in a pandemic during the course of which there was good exposure. There was a 52% reduction and 76.4% reduction in RSV medically associated LRTI in Pfizer and Nirsevimab groups respectively. In severe RSV, the point estimates were 71% and 79% for Pfizer and Nirsevimab groups respectively. For every 25 children given Nirsevimab, 1 child would be protected against RSV LRTI. For severe RSV, 75 children need to get a dose of Nirsevimab to prevent one case of severe RSV and 66 hospitalizations. Studies on the 150 days post dose and efficacy of Nirsevimab and RSV preF maternal vaccination have demonstrated that 8% reduction in all-cause LRTI and 58% reduction in all-cause RSV hospitalization. The Pfizer for preF maternal vaccine did not demonstrate any efficacy against all-cause LRTI. The children that develop a lower respiratory illness are more likely to have subsequent respiratory illness. Children who develop RSV in the first year of life are more likely to have recurrent breathing episodes. A study conducted in South Africa has demonstrated that children who had LRTI that were ambulatory or hospitalized, irrespective of whether it was RSV positive or negative, some of these children had recurrent hospitalization for LRTI which was more accentuated in children with RSV or without RSV that were hospitalized. As compared to children that never had a LRTI episode, children that had LRTI episodes of any severity were 7.74 times more likely to have another wheezing episode or recurrent wheezing episodes. When comparing all-cause hospitalized LRTI versus ambulatory LRTI, a two-fold greater risk was observed. When comparing RSV LRTI versus non-RSV, the former were 2.74 times more likely to suffer subsequent episodes of wheezing. Randomized controlled studies on the effect of Palivizumab showed that children that were randomized to Palivizumab had 60% lower number of days in hospitalization and about 50% less likely to have recurrent episodes of LRTI. One of the risk factors of premature death among adults due to respiratory illness was early childhood LRTI before the age of two years where there was a twofold increased risk. When an individual is infected with the virus, RSV influenza, they are more likely to acquire pneumococcus, there increased density of colonization and they are also more likely to have increased micro aspiration into the lung. with the viral infection of the lung, there impairment in the innate immunity of the lung and depletion of the alveolar macrophages which occurs when the virus is being shed.The micro aspiration leads to weakened defences which can lead to diseases. The impairment of the innate immune system and the susceptibility to superimposed bacterial infection extends beyond a period when the virus stops shedding. A study on respiratory viruses in children has shown that when children receive a pneumococcal conjugate vaccine for RSV, they are 30-33% less likely to be hospitalized for RSV associated pneumonia. The reason for this was that the vaccine was not only protecting against the respiratory viral infections but also the superimposed bacterial infection. There is data that shows that by preventing respiratory viral infections we can prevent superimposed bacterial infection. A study on influenza vaccination in pregnant women showed that vaccination of pregnant women reduces influenza in the mother as well as the child. However, there is a rapid waning of this protection in the child. Most of that benefit is seen in the first 8 weeks which coincides with the rapid waning of antibodies in the baby. There is a 43% reduction in all-cause pneumonia hospitalization in these children which occurs beyond 8 weeks period. In addition, mothers that received influenza vaccines were 50% less likely to acquire pertussis infection. The post-hoc analyses of the safety database in the study on Novavax shows a 50% reduction in pneumonia between 181 and 364 days when there is no circulating RSV infection. There should be equity on the deployment of vaccines in the low and middle-income countries with pneumococcal diseases where they are needed the most. In conclusion, there should be vaccination of pregnant women with RSV preF as well as Nirsevimab protects children from RSV illness and associated hospitalization.There is a need for further investigation whether prevention of RSV will reduce the risk of recurrent LRTI hospitalization and wheezing The public health impact of these interventions will materialize when these vaccines are made affordable to low- and middle-income countries in the immediate future.

European Society of Paediatric Infectious Diseases (ESPID) 2023, 08 - 12 May 2023, Lisbon