Cost-effectiveness of an in-development adult-formulated pneumococcal vaccine in older US adults.

INTRODUCTION: CDC pneumococcal vaccination recommendations for older adults now include either 15- or 20-valent pneumococcal conjugate vaccine (PCV15/PCV20). However, an in-development 21-valent vaccine (PCV21), formulated based on adult pneumococcal disease epidemiology, could substantially increase coverage of disease-causing pneumococcal serotypes, particularly in Black older adults, who are at greater risk. The potential public health impact and cost-effectiveness of PCV21 compared to currently recommended vaccines in older adults is unclear. METHODS: A Markov decision model compared current pneumococcal vaccination recommendations to PCV21 use in Black and non-Black 65-year-old cohorts. CDC Active Bacterial Core surveillance data informed population and serotype-specific pneumococcal disease risk. Vaccine effectiveness was estimated using Delphi panel estimates and clinical trial data, with variation in sensitivity analyses. Potential indirect effects on adult disease from PCV15 childhood vaccination were examined. All model parameters were varied individually and collectively in sensitivity analyses. Scenarios with decreased PCV21 effectiveness and potential COVID-19 pandemic effects were also examined. RESULTS: In the Black cohort, the PCV21 strategy cost $88,478 per quality adjusted life-year (QALY) gained without and $97,952/QALY with childhood PCV15 indirect effects. PCV21 in the non-Black cohort cost $127,436/QALY gained without and $141,358/QALY with childhood PCV15 effects. Current recommendation strategies were economically unfavorable, regardless of population or indirect childhood vaccination effects. Results favoring PCV21 use were robust in sensitivity analyses and alternative scenarios. CONCLUSION: An in-development PCV21 vaccine would likely be economically and clinically favorable compared to currently recommended pneumococcal vaccines in older adults. While PCV21 was more favorable in Black cohort analyses, results for both Black and non-Black populations were economically reasonable, highlighting the potential importance of adult-specific pneumococcal vaccine formulations and, pending further investigation, potentially justifying a future general population recommendation for PCV21 use in older adults.

Modelling the impact of COVID-19 and routine MenACWY vaccination on meningococcal carriage and disease in the UK.

Country-wide social distancing and suspension of non-emergency medical care due to the COVID-19 pandemic will undoubtedly have affected public health in multiple ways. While non-pharmaceutical interventions are expected to reduce the transmission of several infectious diseases, severe disruptions to healthcare systems have hampered diagnosis, treatment, and routine vaccination. We examined the effect of this disruption on meningococcal disease and vaccination in the UK. By adapting an existing mathematical model for meningococcal carriage, we addressed the following questions: What is the predicted impact of the existing MenACWY adolescent vaccination programme? What effect might social distancing and reduced vaccine uptake both have on future epidemiology? Will catch-up vaccination campaigns be necessary? Our model indicated that the MenACWY vaccine programme was generating substantial indirect protection and suppressing transmission by 2020. COVID-19 social distancing is expected to have accelerated this decline, causing significant long-lasting reductions in both carriage prevalence of meningococcal A/C/W/Y strains and incidence of invasive meningococcal disease. In all scenarios modelled, pandemic social mixing effects outweighed potential reductions in vaccine uptake, causing an overall decline in carriage prevalence from 2020 for at least 5 years. Model outputs show strong consistency with recently published case data for England.

[Pneumococcal conjugate vaccines in pediatrics, its impact on Public Health]. / Vacunas conjugadas contra neumococo en pediatría, su impacto en la Salud Pública.

Streptococcus pneumoniae (also known as pneumococcus) is part of the natural bacterial flora of the nasal and pharyngeal mucosa, colonizes mainly the nasopharynx, and causes this carriage to precede pneumococcal disease, thus becoming the main source of propagation among people, especially in children. Since 1983, when the first 23-component anti-pneumococcal vaccine was authorized, different conjugated vaccines have been developed according to the circulating serotypes that cause invasive pneumococcal diseases (IPD), reducing the incidence and mortality of these diseases considerably. In November 2021, a group of experts held a virtual meeting to update and analyze the impact that pneumococcal vaccines have generated on the countries' public health, especially during the COVID-19 pandemic. The recommendations that emerged included the need to look for alternatives in serotype-independent vaccines after the introduction of pneumococcal conjugate vaccines (PCV) in the national immunization schedules, as well as to strengthen the surveillance of serotypes, focusing on those not included in the current vaccines. The objective of this report is to communicate the conclusions of the group of experts that in November 2021 analyzed the impact of pneumococcal vaccines on public health in the countries, in order to generate recommendations applicable in Latin America.

A Phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of V114 compared with PCV13 in healthy infants (PNEU-PED-EU-1).

BACKGROUND: V114 (15-valent pneumococcal conjugate vaccine [PCV]) contains all serotypes in 13-valent PCV (PCV13) and additional serotypes 22F and 33F. This study evaluated safety and immunogenicity of V114 compared with PCV13 in healthy infants, and concomitant administration with DTPa-HBV-IPV/Hib and rotavirus RV1 vaccines. METHODS: V114 and PCV13 were administered in a 2+1 schedule at 2, 4, and 11-15 months of age. Adverse events (AEs) were collected on Days 1-14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series (PPS), immediately prior to a toddler dose, and 30 days post-toddler dose (PTD). Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for the two additional serotypes. RESULTS: 1184 healthy infants 42-90 days of age were randomized 1:1 to V114 (n = 591) or PCV13 (n = 593). Proportions of participants with solicited AEs and serious AEs were comparable between vaccination groups. V114 met pre-specified non-inferiority criteria for all 13 shared serotypes, based on the difference in proportions of participants with serotype-specific IgG concentrations ≥0.35 µg/mL (response rate; lower bound of two-sided 95% confidence interval [CI] >-10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5), and pre-specified superiority criteria for serotypes 22F and 33F (lower bound of two-sided 95% CI >10.0 for response rates and >2.0 for GMC ratios). Antibody responses to DTPa-HBV-IPV/Hib and RV1 vaccines met pre-specified non-inferiority criteria, based on antigen-specific response rates to DTPa-HBV-IPV/Hib and anti-rotavirus IgA geometric mean titers. CONCLUSIONS: After a 2+1 schedule, V114 elicited non-inferior immune responses to 13 shared serotypes and superior responses to the two additional serotypes compared with PCV13, with comparable safety profile. These results support the routine use of V114 in infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04031846; EudraCT: 2018-003787-31.

Randomized trial to evaluate the safety, tolerability, and immunogenicity of a booster (third dose) of BNT162b2 COVID-19 vaccine coadministered with 20-valent pneumococcal conjugate vaccine in adults ≥65 years old.

BACKGROUND: Older adults are at increased risk of adverse outcomes from pneumococcal disease and COVID-19. Vaccination is an established strategy for preventing both illnesses. This study evaluated the safety and immunogenicity of coadministration of the 20-valent pneumococcal conjugate vaccine (PCV20) and a booster (third dose) of BNT162b2 COVID-19 vaccine. METHODS: This phase 3, randomized, double-blind, multicentre study included 570 participants aged ≥65 years randomized 1:1:1 to PCV20 and BNT162b2 coadministered, or PCV20 or BNT162b2 only (administered with saline for blinding). Primary safety endpoints included local reactions, systemic events, adverse events (AEs) and serious AEs (SAEs). Secondary objectives were immunogenicity of PCV20 and BNT162b2 when administered together or separately. RESULTS: Coadministration of PCV20 and BNT162b2 was well tolerated. Local reactions and systemic events were generally mild-moderate; injection-site pain and fatigue were the most frequent local and systemic events, respectively. AE and SAE rates were low and similar across groups. No AEs led to discontinuation; no SAEs were considered vaccination-related. Robust immune responses were observed, with opsonophagocytic activity geometric mean fold rises (GMFRs; from baseline to 1 month) of 2.5-24.5 and 2.3-30.6 across PCV20 serotypes in Coadministration and PCV20-only groups, respectively. GMFRs for full-length S-binding IgG of 35.5 and 39.0, and for neutralizing titres against SARS-CoV-2-wild type virus of 58.8 and 65.4, were observed in the Coadministration and BNT162b2-only groups, respectively. CONCLUSIONS: Safety and immunogenicity of coadministered PCV20 and BNT162b2 were similar to those of PCV20 or BNT162b2 administered alone, suggesting that the 2 vaccines may be coadministered. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04887948.

Immunogenicity and safety of a 10-valent pneumococcal conjugate vaccine administered as a 2 + 1 schedule to healthy infants in The Gambia: a single-centre, double-blind, active-controlled, randomised, phase 3 trial.

BACKGROUND: Three pneumococcal conjugate vaccines (PCVs) are currently licensed and WHO prequalified for supply by UN agencies. Here, we aimed to investigate the safety and immunogenicity of SIIPL-PCV compared with PHiD-CV and PCV13, when administered to infants according to a 2 + 1 schedule. METHODS: This single-centre, double-blind, active-controlled, randomised, phase 3 trial was done in Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine clinical trial facilities within two government health centres in the western region of The Gambia. Healthy, PCV-naive infants aged 6-8 weeks were enrolled if they weighed at least 3·5 kg and had no clinically significant health complaints, as determined by history and clinical examination. Eligible infants were randomly assigned (1:1:1) to receive either SIIPL-PCV, PHiD-CV, or PCV13 using permuted blocks of variable size. Parents and the trial staff assessing all study outcomes were masked to vaccine group. The first PCV vaccine was given with other routine Expanded Programme on Immunization vaccines when infants were aged 6-8 weeks (visit 1). At visit 2, routine vaccines alone (without a PCV) were administered. At visit 3, the second dose of the PCV was administered alongside other routine vaccines. At visit 4, a blood sample was collected. Visits 1-4 took place at intervals of 4 weeks. The booster PCV was administered at age 9-18 months (visit 5), with final follow-up 4 weeks after the booster (visit 6). The primary immunogenicity outcome compared the serotype-specific IgG geometric mean concentrations (GMCs) generated by SIIPL-PCV with those generated by PHiD-CV and PCV13, 4 weeks after the booster. We used descriptive 95% CIs without adjustment for multiplicity. Immunogenicity analyses were done in the per protocol population (defined as all children who received all the assigned study vaccines, who had an immunogenicity measurement available, and who had no protocol deviations that might interfere with the immunogenicity assessment). This trial was registered with the Pan African Clinical Trials Registry, PACTR201907754270299, and ClinicalTrials.gov, NCT03896477. FINDINGS: Between July 18 and Nov 14, 2019, 745 infants were assessed for study eligibility. Of these, 85 infants (11%) were ineligible and 660 (89%) were enrolled and randomly assigned to receive SIIPL-PCV (n=220), PHiD-CV (n=220), or PCV13 (n=220). 602 infants (91%) were included in the per protocol immunogenicity population. The median age at vaccination was 46 days (range 42-56). 342 infants (52%) were female and 318 (48%) were male. Post-booster serotype-specific IgG GMCs generated by SIIPL-PCV ranged from 1·54 µg/mL (95% CI 1·38-1·73) for serotype 5 to 12·46 µg/mL (11·07-14·01) for serotype 6B. Post-booster GMCs against shared serotypes generated by PHiD-CV ranged from 0·80 µg/mL (0·72-0·88) for serotype 5 to 17·31 µg/mL (14·83-20·20) for serotype 19F. Post-booster GMCs generated by PCV13 ranged from 2·04 µg/mL (1·86-2·24) for serotype 5 to 15·54 µg/mL (13·71-17·60) for serotype 6B. Post-booster IgG GMCs generated by SIIPL-PCV were higher than those generated by PHiD-CV for seven of the eight shared serotypes (1, 5, 6B, 7F, 9V, 14, and 23F). The GMC generated by serotype 19F was higher after PHiD-CV. The SIIPL-PCV to PHiD-CV GMC ratios for shared serotypes ranged from 0·64 (95% CI 0·52-0·79) for serotype 19F to 2·91 (2·47-3·44) for serotype 1. The serotype 1 GMC generated by SIIPL-PCV was higher than that generated by PCV13, whereas serotype 5, 6A, 19A, and 19F GMCs were higher after PCV13. The SIIPL-PCV to PCV13 GMC ratios ranged from 0·72 (0·60-0·87) for serotype 19A to 1·44 (1·23-1·69) for serotype 1. INTERPRETATION: SIIPL-PCV was safe and immunogenic when given to infants in The Gambia according to a 2 + 1 schedule. This PCV is expected to provide similar protection against invasive and mucosal pneumococcal disease to the protection provided by PCV13 and PHiD-CV, for which effectiveness data are available. Generating post-implementation data on the impact of SIIPL-PCV on pneumococcal disease endpoints remains important. FUNDING: Bill & Melinda Gates Foundation.

Invasive pneumococcal surveillance to assess the potential benefits of extended spectrum conjugate vaccines (PCV15/PCV20) in older adults.

The introduction of pneumococcal conjugate vaccines (PCV) into the childhood vaccination programme has reduced invasive pneumococcal disease (IPD). Although anticipated from data elsewhere, surveillance in Ireland has confirmed reductions in IPD amongst those ⩾65 years of age due to a decline of PCV serotypes in this age group. Currently, direct protection against IPD in the elderly is focused on immunisation with the 23-valent pneumococcal polysaccharide vaccine (PPV23). However, immunity may not be as effective as with PCV and, furthermore, PPV23 uptake is poor in Ireland. Hence, consideration should be given to providing a PCV to this age group.

Assembly of Immunogenic Protein Particles toward Advanced Synthetic Vaccines.

Immunogenic carrier proteins such as the non-toxic diphtheria toxin variant, cross-reacting material 197 (CRM197), are widely used in subunit vaccine formulations to boost immunogenicity of chemically conjugated antigens. Conjugate vaccines are inherently expensive due to laborious manufacturing steps. Here, this work develops a particulate vaccine platform based on using engineered Escherichia coli to assemble CRM197-antigen fusion proteins into discrete submicron-sized particles. This approach enables precise loading of diverse antigens and epitopes enhancing their immunogenicity. A cost-effective, high-yield, and scalable biomanufacturing process is developed. Purified particulate CRM197-antigen vaccines are ambient-temperature stable. CRM197 particles incorporating pathogen-specific antigens or epitopes from SARS-CoV-2, Streptococcus pyogenes (group A), and Mycobacterium tuberculosis induced cell-mediated and humoral immune responses mediating protective immunity in respective animal models of infection. The CRM197 particle vaccine platform is versatile, enabling co-delivery of selected antigens/epitopes together with immunogenic CRM197 as discrete stable particles avoiding laborious manufacture of soluble CRM197 and antigen followed by chemical conjugation.

Safety, tolerability, and immunogenicity of V114 pneumococcal vaccine compared with PCV13 in a 2+1 regimen in healthy infants: A phase III study (PNEU-PED-EU-2).

BACKGROUND: This phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in healthy infants. V114 contains all 13 serotypes in PCV13 and additional serotypes 22F and 33F. METHODS: Healthy infants were randomized to two primary doses and one toddler dose (2+1 regimen) of V114 or PCV13 at 3, 5, and 12 months of age; diphtheria, tetanus, pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib), hepatitis B (HepB) vaccine was administered concomitantly. Adverse events (AEs) were collected on Days 1-14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series, immediately prior to toddler dose, and 30 days post-toddler dose. Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for serotypes 22F and 33F. RESULTS: 1191 healthy infants were randomized to V114 (n = 595) or PCV13 (n = 596). Proportions of participants with solicited AEs and serious AEs were comparable between groups. V114 met non-inferiority criteria for 13 shared serotypes, based on difference in proportions with serotype-specific IgG ≥0.35 µg/mL (lower bound of two-sided 95% confidence interval [CI] >-10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5) at 30 days post-toddler dose. V114 met superiority criteria for serotypes 22F and 33F, based on response rates (lower bound of two-sided 95% CI >10.0) and IgG GMC ratios (lower bound of two-sided 95% CI >2.0) at 30 days post-toddler dose. Antibody responses to DTaP-IPV-Hib-HepB met non-inferiority criteria, based on antigen-specific response rates. CONCLUSION: A two-dose primary series plus toddler dose of V114 was well-tolerated in healthy infants. Compared with PCV13, V114 provided non-inferior immune responses to 13 shared serotypes and superior immune responses to additional serotypes 22F and 33F.

Identifying UK travellers at increased risk of developing pneumococcal infection: a novel algorithm.

BACKGROUND: In 2016, the travel subcommittee of the UK Joint Committee on Vaccination and Immunisation (JCVI) recommended that 13-valent PCV (PCV13) could be offered to travellers aged over 65 years, visiting countries without infant PCV immunization programmes. This study aimed to identify, collate and review the available evidence to identify specific countries where UK travellers might be at an increased risk of developing pneumococcal infection. The data were then used to develop an algorithm, which could be used to facilitate implementation of the JCVI recommendation. METHODS: We conducted a systematic search of the published data available for pneumococcal disease, PCV vaccine implementation, coverage data and programme duration by country. The primary data sources used were World Health Organization databases and the International Vaccine Access Centre Vaccine Information and Epidemiology Window-hub database. Based on the algorithm, the countries were classified into 'high overall risk', 'intermediate overall risk' and 'low overall risk' from an adult traveller perspective. This could determine whether PCV13 should be recommended for UK adult travellers. RESULTS: A data search for a total of 228 countries was performed, with risk scores calculated for 188 countries. Overall, 45 countries were classified as 'high overall risk', 86 countries as 'intermediate overall risk', 57 countries as 'low overall risk' and 40 countries as 'unknown'. CONCLUSION: To our knowledge this is the first attempt to categorize the risk to UK adult travellers of contracting pneumococcal infection in each country, globally. These findings could be used by national travel advisory bodies and providers of travel vaccines to identify travellers at increased risk of pneumococcal infection, who could be offered PCV immunization.

Self-Adjuvanting Protein Vaccine Conjugated with a Novel Synthetic TLR4 Agonist on Virus-Like Liposome Induces Potent Immunity against SARS-CoV-2.

Exploring potent adjuvants and new vaccine strategies is crucial for the development of protein vaccines. In this work, we synthesized a new TLR4 agonist, structurally simplified lipid A analogue GAP112, as a potent built-in adjuvant to improve the immunogenicity of SARS-CoV-2 spike RBD protein. The new TLR4 agonist GAP112 was site-selectively conjugated on the N-terminus of RBD to construct an adjuvant-protein conjugate vaccine in a liposomal formulation. It is the first time that a TLR4 agonist is site-specifically and quantitatively conjugated to a protein antigen. Compared with an unconjugated mixture of GAP112/RBD, a two-dose immunization of the GAP112-RBD conjugate vaccine strongly activated innate immune cells, elicited a 223-fold increase in RBD-specific antibodies, and markedly enhanced T-cell responses. Antibodies induced by GAP112-RBD also effectively cross-neutralized SARS-CoV-2 variants (Delta/B.1.617.2 and Omicron/B.1.1.529). This conjugate strategy provides an effective method to greatly enhance the immunogenicity of antigen in protein vaccines against SARS-CoV-2 and other diseases.

Vaccine Impact and Effectiveness of Meningococcal Serogroup ACWY Conjugate Vaccine Implementation in the Netherlands: A Nationwide Surveillance Study.

BACKGROUND: In response to the recent serogroup W invasive meningococcal disease (IMD-W) epidemic in the Netherlands, meningococcal serogroup C (MenC) conjugate vaccination for children aged 14 months was replaced with a MenACWY conjugate vaccination, and a mass campaign targeting individuals aged 14-18 years was executed. We investigated the impact of MenACWY vaccination implementation in 2018-2020 on incidence rates and estimated vaccine effectiveness (VE). METHODS: We extracted IMD cases diagnosed between July 2014 and December 2020 from the national surveillance system. We calculated age group-specific incidence rate ratios by comparing incidence rates before (July 2017-March 2018) and after (July 2019-March 2020) MenACWY vaccination implementation. We estimated VE in vaccine-eligible cases using the screening method. RESULTS: Overall, the IMD-W incidence rate declined by 61% (95% confidence interval [CI], 40 to 74). It declined by 82% (95% CI, 18 to 96) in the vaccine-eligible age group (individuals aged 15-36 months and 14-18 years) and by 57% (95% CI, 34 to 72) in vaccine-noneligible age groups. VE was 92% (95% CI, -20 to 99.5) in vaccine-eligible toddlers (aged 15-36 months). No IMD-W cases were reported in vaccine-eligible teenagers after the campaign. CONCLUSIONS: The MenACWY vaccination program was effective in preventing IMD-W in the target population. The IMD-W incidence reduction in vaccine-noneligible age groups may be caused by indirect effects of the vaccination program. However, disentangling natural fluctuation from vaccine effect was not possible. Our findings encourage the use of toddler and teenager MenACWY vaccination in national immunization programs.

Facilitating access to pneumococcal vaccine for people living with HIV: an experience report.

OBJECTIVE: The article describes a strategy to facilitate access to pneumococcal conjugate vaccine 13 (PCV-13) for people living with HIV/AIDS (PLHIV) during the COVID-19 pandemic. METHOD: report on the experience regarding the organization of a care service for PLHIV in the city of São Paulo to facilitate access to PCV-13 in the framework of the 2020 influenza vaccination campaign during the COVID-19 pandemic. RESULTS: through the integration between a PLHIV care service and an Immunization Center (CRIE in Portuguese), it was possible to offer PCV-13 to PLHIV at the point of care, reducing physical barriers to access to immunization. Thus, of the 1,906 PLHIV who passed through the service during the period March 23-July 31, 2020, 84.4% (1,609) received the influenza vaccine, PCV-13 or both. Of the 1609 vaccinated, 50.6% (814) were eligible and received PCV-13. CONCLUSION: offering the vaccine at the point of care and orienting PLHIV on the importance of vaccination as a disease prevention strategy, identifying those eligible to receive it, was an important action carried out by the institution together with the nursing team, as a strategy to facilitate access to vaccination.

Meningococcal disease in North America: Updates from the Global Meningococcal Initiative.

This review summarizes the recent Global Meningococcal Initiative (GMI) regional meeting, which explored meningococcal disease in North America. Invasive meningococcal disease (IMD) cases are documented through both passive and active surveillance networks. IMD appears to be decreasing in many areas, such as the Dominican Republic (2016: 18 cases; 2021: 2 cases) and Panama (2008: 1 case/100,000; 2021: <0.1 cases/100,000); however, there is notable regional and temporal variation. Outbreaks persist in at-risk subpopulations, such as people experiencing homelessness in the US and migrants in Mexico. The recent emergence of ß-lactamase-positive and ciprofloxacin-resistant meningococci in the US is a major concern. While vaccination practices vary across North America, vaccine uptake remains relatively high. Monovalent and multivalent conjugate vaccines (which many countries in North America primarily use) can provide herd protection. However, there is no evidence that group B vaccines reduce meningococcal carriage. The coronavirus pandemic illustrates that following public health crises, enhanced surveillance of disease epidemiology and catch-up vaccine schedules is key. Whole genome sequencing is a key epidemiological tool for identifying IMD strain emergence and the evaluation of vaccine strain coverage. The Global Roadmap on Defeating Meningitis by 2030 remains a focus of the GMI.

Cost-effectiveness analyses of 15- and 20-valent pneumococcal conjugate vaccines for Japanese elderly.

BACKGROUND: Despite the 23-valent pneumococcal polysaccharide vaccine (PPSV23) vaccination programme implementation, pneumococcal disease (PD) remains an important cause of morbidity and mortality among the elderly in Japan, particularly since childhood pneumococcal conjugate vaccine (PCV) vaccination programme continues to alter the serotype PD distribution among the elderly. Recently, in the United States, PCV15/PCV20 were recommended for adults aged ≥ 65 years and those aged 19-64 years with certain underlying conditions. In Japan, PCV15 is under the approval application process and PCV20 undergoing clinical trials, which has warranted the need in evaluating their value for money. METHODS: We conducted cost-effectiveness analyses with Markov model and calculated incremental cost-effectiveness ratios of PCV15/PCV20 vaccination programme compared to status quo from payers' perspective. Transition probabilities and utility weights in estimating quality-adjusted life-year (QALY), and disease treatment costs were either estimated or obtained from literature. To reflect the situation of COVID-19 pandemic, epidemiological data from 2020 and beyond were used. RESULTS: Compared to the current vaccination programme, PCV20 vaccination programme gained more QALYs with less cost, while PCV15 vaccination programme cost ¥35,020 (US$318, US$1 = ¥110) to gain an additional QALY. Replacing PPSV23 vaccination programme with PCV20 vaccination programme is cost-saving. One-way sensitivity analyses revealed that lower VE limits of PCVs against non-bacteremic pneumonia (NBP) have large impact to change the result from PCV20 vaccination programme dominated PPSV23 vaccination programme to PPSV23 vaccination programme dominated PCV20 vaccination programme. CONCLUSION: In the COVID-19 era, replacing current PPSV23 with a single-dose PCV15- or PCV20 immunisation programme for 65-year-old adults in Japan is highly cost-effective, while the PCV 20 vaccination programme was observed to be more favourable.

Effect of COVID-19 Pandemic on Invasive Pneumococcal Disease in Children, Catalonia, Spain.

We analyzed the effect of COVID-19 on healthcare demand and invasive pneumococcal disease in children in Catalonia, Spain. Compared with 2018-2019, we noted large reductions in healthcare activities and incidence of invasive pneumococcal disease in 2020. These changes likely resulted from nonpharmaceutical measures implemented during the COVID-19 pandemic.

A policy review of the introduction of the MenACWY vaccine in toddlers across multiple countries.

INTRODUCTION: Immunization is the best strategy to protect individuals from invasive meningococcal disease (IMD). To support decision-making around immunization, this paper considers what has led four countries and regions of two more to introduce the quadrivalent MenACWY vaccine in toddlers (ages 12-24 months). AREAS COVERED: A narrative literature review was conducted to identify countries that have introduced a MenACWY vaccination program for toddlers. Information from peer-reviewed publications, reports, and policy documents for each identified country was extracted. Australia, Chile, the Netherlands, Switzerland, and regions of Italy and Spain have introduced the MenACWY vaccine in their toddler programs, driven by the rising incidence of MenW and MenY and the vaccine's ability to provide protection against other serogroups. Australia and the Netherlands considered the economic impacts of implementing a MenACWY toddler vaccination program. Vaccination uptake and effects are reported for three countries; however, in two, isolating the vaccine's effect from the collateral effect of COVID-related measures is difficult. EXPERT OPINION: Increased convergence of vaccination policies and programs is needed internationally, as IMD recognizes no borders.PL AIN LANGUAGE SUMMARYVaccination is the best defense against meningitis, a deadly disease. While someone of any age can contract it, children 0-24 months of age are disproportionately affected. The increasing number of cases of meningitis has led four countries plus regions of two more to introduce into their vaccination schedules for toddlers (ages 12-24 months) a vaccine that protects against four different serogroups rather than one serogroup alone. This paper considers what has driven that shift.

Safety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months to 12 years in Malawi: a nested substudy of a double-blind, randomised controlled trial.

BACKGROUND: Typhoid fever is a substantial public health problem in Africa, yet there are few clinical trials of typhoid conjugate vaccine (TCV). We assessed immunogenicity and safety of Typbar TCV in Malawi. METHODS: This substudy was nested within a phase 3, double-blind, parallel design, randomised controlled trial of TCV in children from Ndirande Health Centre in Ndirande township, Blantyre, Malawi. To be eligible, participants had to be aged between 9 months and 12 years with no known immunosuppression or chronic health conditions, including HIV or severe malnutrition; eligible participants were enrolled into three strata of approximately 200 children (9-11 months, 1-5 years, and 6-12 years), randomly assigned (1:1) to receive TCV or control (meningococcal serogroup A conjugate vaccine [MCV-A]) intramuscularly. Serum was collected before vaccination and at 28 days and 730-1035 days after vaccination to measure anti-Vi antibodies by ELISA. Because of COVID-19, day 730 visits were extended up to 1035 days. This nested substudy evaluated reactogenicity, safety, and immunogenicity by age stratum. Safety outcomes, analysed in the intention-to-treat population, included solicited adverse events within 7 days of vaccination (assessed on 3 separate days) and unsolicited adverse events within 28 days of vaccination. This trial is registered with ClinicalTrials.gov, NCT03299426. FINDINGS: Between Feb 22 and Sept 6, 2018, 664 participants were screened, and 631 participants were enrolled and randomly assigned (320 to the TCV group and 311 to the MCV-A group). 305 participants in the TCV group and 297 participants in the MCV-A group were vaccinated. Among TCV recipients, anti-Vi IgG geometric mean titres increased more than 500 times from 4·2 ELISA units (EU)/mL (95% CI 4·0-4·4) at baseline to 2383·7 EU/mL (2087·2-2722·3) at day 28, then decreased to 48·0 EU/mL (39·9-57·8) at day 730-1035, remaining more than 11 times higher than baseline. Among MCV-A recipients, anti-Vi IgG titres remained unchanged: 4·3 EU/mL (4·0-4·5) at baseline, 4·4 EU/mL (4·0-4·7) on day 28, and 4·6 EU/mL (4·2-5·0) on day 730-1035. TCV and MCV-A recipients had similar solicited local (eight [3%] of 304, 95% CI 1·3-5·1 and three [1%] of 293, 0·4-3·0) and systemic (27 [9%] of 304, 6·2-12·6 and 27 [9%] of 293, 6·4-13·1) reactogenicity. Related unsolicited adverse events occurred similarly in TCV and MCV-A recipients in eight (3%) of 304 (1·3-5·1) and eight (3%) of 293 (1·4-5·3). INTERPRETATION: This study provides evidence of TCV safety, tolerability, and immunogenicity up to 730-1035 days in Malawian children aged 9 months to 12 years. FUNDING: Bill & Melinda Gates Foundation.

Effect of pneumococcal conjugate vaccines and SARS-CoV-2 on antimicrobial resistance and the emergence of Streptococcus pneumoniae serotypes with reduced susceptibility in Spain, 2004-20: a national surveillance study.

BACKGROUND: Epidemiological studies are necessary to explore the effect of current pneumococcal conjugate vaccines (PCVs) against antibiotic resistance, including the rise of non-vaccine serotypes that are resistant to antibiotics. Hence, epidemiological changes in the antimicrobial pattern of Streptococcus pneumoniae before and during the first year of the COVID-19 pandemic were studied. METHODS: In this national surveillance study, we characterised the antimicrobial susceptibility to a panel of antibiotics in 3017 pneumococcal clinical isolates with reduced susceptibility to penicillin during 2004-20 in Spain. This study covered the early and late PCV7 periods; the early, middle, and late PCV13 periods; and the first year of the COVID-19 pandemic, to evaluate the contribution of PCVs and the pandemic to the emergence of non-vaccine serotypes associated with antibiotic resistance. FINDINGS: Serotypes included in PCV7 and PCV13 showed a decline after the introduction of PCVs in Spain. However, an increase in non-PCV13 serotypes (mainly 11A, 24F, and 23B) that were not susceptible to penicillin promptly appeared. A rise in the proportion of pneumococcal strains with reduced susceptibility to ß-lactams and erythromycin was observed in 2020, coinciding with the emergence of SARS-CoV-2. Cefditoren was the ß-lactam with the lowest minimum inhibitory concentration (MIC)50 or MIC90 values, and had the highest proportion of susceptible strains throughout 2004-20. INTERPRETATION: The increase in non-PCV13 serotypes associated with antibiotic resistance is concerning, especially the increase of penicillin resistance linked to serotypes 11A and 24F. The future use of PCVs with an increasingly broad spectrum (such as PCV20, which includes serotype 11A) could reduce the impact of antibiotic resistance for non-PCV13 serotypes. The use of antibiotics to prevent co-infections in patients with COVID-19 might have affected the increased proportion of pneumococcal-resistant strains. Cefotaxime as a parenteral option, and cefditoren as an oral choice, were the antibiotics with the highest activity against non-PCV20 serotypes. FUNDING: The Spanish Ministry of Science and Innovation and Meiji-Pharma Spain. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Psychosocial and organizational barriers and facilitators of meningococcal vaccination (MenACWY) acceptance among adolescents and parents during the Covid-19 pandemic: a cross-sectional survey.

BACKGROUND: This study aimed to identify differences and similarities among adolescents and parents in various psychosocial factors influencing meningococcal ACWY (MenACWY) vaccination acceptance. Besides, the impact of the Covid-19 pandemic was assessed as well as resulting organizational adjustments. METHODS: We conducted a cross-sectional survey among adolescents that attended the appointment for the MenACWY vaccination in South Limburg between May and June 2020, and their parents. Independent t-tests and χ2 test were performed to explore differences in psychosocial and organisational factors between adolescents and parents. RESULTS: In total, 592 adolescents (20%) and 1197 parents (38%) filled out the questionnaire. Adolescents scored lower on anticipated negative affect towards MenACWY vaccination refusal [t (985.688) = - 9.32; ρ < 0.001], moral norm towards MenACWY vaccination acceptance [t (942.079) = - 10.38; ρ < 0.001] and knowledge about the MenACWY vaccination and meningococcal disease [t (1059.710) = - 11.24; ρ < 0.001]. Both adolescents and parents reported a social norm favouring accepting childhood vaccinations, but adolescent scored higher [t (1122.846) = 23.10; ρ < 0.001]. The Covid-19 pandemic did barely influence the decision to accept the MenACWY vaccination. Only 6% of the participants indicated that Covid-19 influenced their decision. In addition, the individual vaccination appointment was rated very positive. Most adolescents (71.5%) and parents (80.6%) prefer future vaccinations to be offered individually rather than having mass vaccinations sessions. CONCLUSIONS: This study provides an indication of which psychosocial and organisational factors should be addressed in future MenACWY vaccination campaigns. Individual vaccination appointments for adolescents should be considered, taking the costs and logistical barriers into account.