The Quest for a Respiratory Syncytial Virus Vaccine for Older Adults: Thinking beyond the F Protein.

Respiratory syncytial virus (RSV) is a common cause of paediatric respiratory tract infection and causes a significant health burden in older adults. Natural immunity to RSV is incomplete, permitting recurrent symptomatic infection over an individual's lifespan. When combined with immunosenescence, this increases older adults' susceptibility to more severe disease symptoms. As RSV prophylaxis is currently limited to infants, older adults represent an important target population for RSV vaccine development. The relationship between RSV and our immune systems is complex, and these interactions require deeper understanding to tailor an effective vaccine candidate towards older adults. To date, vaccine candidates targeting RSV antigens, including pre-F, F, G (A), G (B), M2-1, and N, have shown efficacy against RSV infection in older adults in clinical trial settings. Although vaccine candidates have demonstrated robust neutralising IgG and cellular responses, it is important that research continues to investigate the RSV immune response in order to further understand how the choice of antigenic target site may impact vaccine effectiveness. In this article, we discuss the Phase 3 vaccine candidates being tested in older adults and review the hurdles that must be overcome to achieve effective protection against RSV.

The epidemiology of infectious diseases in Europe in 2020 versus 2017-2019 and the rise of tick-borne encephalitis (1995-2020).

Health control measures instituted in 2020 to mitigate the COVID-19 pandemic decreased the case numbers of many infectious diseases across Europe. One notable exception was tick-borne encephalitis (TBE). In Austria, Germany, Switzerland, Lithuania, and the Czech Republic, the upturn was significantly higher compared to the average of the three years previously (P<0.05), with increases of 88%, 48%, 51%, 28%, and 18%, respectively. Six countries reported TBE incidences of ≥5 cases/100,000, defined as highly endemic by the World Health Organization (WHO). Possible factors contributing to this surge may include increased participation in outdoor activities in endemic regions and increased tick counts/tick activity. In highly endemic regions, the WHO recommends that vaccination be offered to all age groups, including children.

The changing epidemiology of human monkeypox-A potential threat? A systematic review.

Monkeypox, a zoonotic disease caused by an orthopoxvirus, results in a smallpox-like disease in humans. Since monkeypox in humans was initially diagnosed in 1970 in the Democratic Republic of the Congo (DRC), it has spread to other regions of Africa (primarily West and Central), and cases outside Africa have emerged in recent years. We conducted a systematic review of peer-reviewed and grey literature on how monkeypox epidemiology has evolved, with particular emphasis on the number of confirmed, probable, and/or possible cases, age at presentation, mortality, and geographical spread. The review is registered with PROSPERO (CRD42020208269). We identified 48 peer-reviewed articles and 18 grey literature sources for data extraction. The number of human monkeypox cases has been on the rise since the 1970s, with the most dramatic increases occurring in the DRC. The median age at presentation has increased from 4 (1970s) to 21 years (2010-2019). There was an overall case fatality rate of 8.7%, with a significant difference between clades-Central African 10.6% (95% CI: 8.4%- 13.3%) vs. West African 3.6% (95% CI: 1.7%- 6.8%). Since 2003, import- and travel-related spread outside of Africa has occasionally resulted in outbreaks. Interactions/activities with infected animals or individuals are risk behaviors associated with acquiring monkeypox. Our review shows an escalation of monkeypox cases, especially in the highly endemic DRC, a spread to other countries, and a growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa highlights the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.

A systematic review of invasive pneumococcal disease vaccine failures and breakthrough with higher-valency pneumococcal conjugate vaccines in children.

INTRODUCTION: The pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV/PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13) protect against vaccine-serotype invasive pneumococcal disease (VT IPD). However, VT IPD can still occur in fully or partially vaccinated children (vaccine failure or breakthrough). We performed a systematic review of vaccine failures and breakthrough IPD with PCV10 and PCV13 in ≤5-year-olds. AREAS COVERED: We searched Scopus/Medline/EMBASE to retrieve articles/abstracts published between 1/2008-7/2019. We excluded reports only including data from ≥6-year-olds, exclusively assessing PCV7-vaccinated children or children with comorbidities. Twenty-six reports (20 PCV13, 1 PCV10, 5 both), covering studies with various designs in six continents, using different schedules, were included. Collectively, they reported 469 VT IPD cases classified as vaccine failures and 403 as breakthrough. Vaccine failure and breakthrough rates were low: 8.4% and 9.3%, respectively, of all IPD in vaccinated children, consistent with the vaccines' high effectiveness. The main serotypes associated with vaccine failure/breakthrough were 19A, 3 and 19F for PCV13 and 14, 6B and vaccine-related 19A and 6A for PCV10. EXPERT OPINION: As we move to vaccines with more serotypes, it is not only important to consider which serotypes are added, but also monitor and address incomplete protection against specific serotypes.

PLAIN LANGUAGE SUMMARYWhat is the context?Pneumococcal conjugate vaccines have been given to children for over 20 years to prevent infections caused by the bacterium Streptococcus pneumoniae (such as pneumonia, meningitis and sepsis).At least 100 different types of S. pneumoniae, so called serotypes, exist, but a relatively small number causes most disease.Two current vaccines (Synflorix, GSK and Prevnar 13, Pfizer) protect against 10 to 13 serotypes and have significantly reduced pneumococcal disease caused by these serotypes.A rise in serotypes not targeted by these vaccines has lessened the vaccines' expected impact.As no vaccine is 100% protective, some serotypes targeted by the current vaccines continue to circulate.What is new?We performed a systematic literature review to evaluate which serotypes are most often associated with invasive disease occurring after receives all planned pneumococcal vaccine doses (vaccine failure) or after a child receives part of the planned vaccine doses (breakthrough).We found that vaccine failures and breakthrough disease were uncommon with both vaccines, irrespective of the administered schedule.A small number of serotypes were responsible for most vaccine failures and breakthrough disease with both vaccines.What is the impact?The low rate of vaccine failures and breakthrough disease observed with the current vaccines confirms their high effectiveness in preventing pneumococcal disease.The primary consideration in developing pneumococcal conjugate vaccines that include more than 13 serotypes will be how additional protection they can provide.Reduced protection against individual serotypes remains a risk.The evaluation of current vaccines demonstrates that incomplete protection against specific serotypes should also be addressed.

One or two doses of hepatitis A vaccine in universal vaccination programs in children in 2020: A systematic review.

BACKGROUND: Hepatitis A virus (HAV) is a global health concern as outbreaks continue to occur. Since 1999, several countries have introduced universal vaccination (UV) of children against HAV according to approved two-dose schedules. Other countries have implemented one-dose UV programs since 2005; the long-term impact of this schedule is not yet known. METHODS: We conducted a systematic literature search in four electronic databases for data published between January 2000 and July 2019 to assess evidence for one-dose and two-dose UV of children with non-live HAV vaccines and describe their global impact on incidence, mortality, and severity of hepatitis A, vaccine effectiveness, vaccine efficacy, and antibody persistence. RESULTS: Of 3739 records screened, 33 peer-reviewed articles and one conference abstract were included. Rapid declines in incidence of hepatitis A and related outcomes were observed in all age groups post-introduction of UV programs, which persisted for at least 14 years for two-dose and six years for one-dose programs according to respective study durations. Vaccine effectiveness was ≥95% over 3-5 years for two-dose programs. Vaccine efficacy was >98% over 0.1-7.5 years for one-dose vaccination. Antibody persistence in vaccinated individuals was documented for up to 15 years (≥90%) and ten years (≥74%) for two-dose and one-dose schedules, respectively. CONCLUSION: Experience with two-dose UV of children against HAV is extensive, demonstrating an impact on the incidence of hepatitis A and antibody persistence for at least 15 years in many countries globally. Because evidence is more limited for one-dose UV, we were unable to draw conclusions on immune response persistence beyond ten years or the need for booster doses later in life. Ongoing epidemiological monitoring is essential in countries implementing one-dose UV against HAV. Based on current evidence, two doses of non-live HAV vaccines are needed to ensure long-term protection.

Interchangeability between pneumococcal conjugate vaccines for pediatric use: a systematic literature review.

Introduction: Evidence on the interchangeability between the two pediatric pneumococcal conjugate vaccines (PCVs) - pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) and 13-valent PCV (PCV13) - is limited but growing. We performed a systematic literature review to summarize evidence for PHiD-CV/PCV13 interchangeability regarding immunogenicity, safety, and effectiveness against pneumococcal disease. Areas covered: Seven records disclosing results from six studies on PHiD-CV/PCV13 interchangeability were identified. Four clinical trials showed that mixed schedules with a PHiD-CV-to-PCV13 switch at boosting or a PCV13-to-PHiD-CV switch during priming or at boosting were immunogenic with no apparent safety concerns. Two observational studies in the context of a programmatic PHiD-CV-to-PCV13 switch showed similarly high effectiveness against overall invasive pneumococcal disease with a mixed PHiD-CV/PCV13 schedule and a PCV13-only schedule. No effectiveness data for a PCV13-to-PHiD-CV switch and no immunogenicity/safety/effectiveness data for a PHiD-CV-to-PCV13 switch during priming were found. Expert opinion: For epidemiological or programmatic reasons, several local/national authorities have switched PCVs in their immunization programs. Consequently, children have received mixed schedules. Although herd immunity may obscure the individual effect, the limited data are reassuring. Additional evidence from these settings - especially effectiveness or impact data - may provide the necessary information for authorities to make informed decisions on interchanging PCVs.

Increasing Burden of Hepatitis A in Adolescents and Adults and the Need for Long-Term Protection: A Review from the Indian Subcontinent.

Hepatitis A, an acute inflammatory liver disease caused by hepatitis A virus (HAV) infection from close contact with infected people, is highly endemic in the Indian subcontinent. Due to poor sanitary conditions, most of the population is exposed to the virus in childhood. At this age, the disease is asymptomatic and provides life-long protection against the disease. Due to rapid socioeconomic development in some areas, however, pockets of the population are reaching adolescence/adulthood without prior exposure to the virus and are thus susceptible to infection. At these ages, infection carries a higher risk of symptomatic disease and complications including mortality. This review of epidemiology and burden of disease studies in the Indian subcontinent, published since 2005, shows increasing evidence of a shift from high to intermediate endemicity in high-income-typically urban-populations. The prevalence of anti-HAV antibodies (previously reported at > 90%) is lower now in adolescents and young adults (e.g., around 80% in Bangladesh and 55% in 5-15 years in India). As a result, HAV is responsible for more acute viral hepatitis predominantly in this age group (e.g., > 15 years: 3.4% in 1999 to 12.3% in 2003 or high socioeconomic status 13-20 years: 27% in 1999 to 62% in 2003), with a greater clinical and economic burden. Numerous outbreaks due to HAV have been reported [e.g., Sri Lanka (2009-2010): > 13,000 affected; Kashmir (2015-2017): 12 outbreaks; Kerala (2012-2016): 84 outbreaks] from water or food contamination. Due to current shifts in endemicity, a growing proportion of the population is no longer exposed in childhood. As the disease remains highly endemic, it also provides a source for more severe disease in susceptible people at an older age and for outbreaks. Well-tolerated and effective vaccines are available and help prevent disease burden and provide long-term protection. These should now be used more widely to protect more patients from the growing disease burden of hepatitis A. FUNDING: GlaxoSmithKline Biologicals SA. Plain language summary available for this article-please see Fig. 1 and the following link: https://doi.org/10.6084/m9.figshare.9963044.Fig. 1Plain Language Summary. Highlights the context of the article, the endemicity shift and the burden of hepatitis A in adolescents and adults and steps to be taken to address the impact of this disease.

Would immunization be the same without cross-reactivity?

"Cross-reactivity" (the observed immune response against pathogen types not specifically targeted by the vaccine antigen composition) and "cross-protection" (clinical protection against related non-vaccine microorganism types) are vaccinology concepts that are attracting renewed interest in the context of disease prevention. National health authorities are collecting mounting evidence of the importance of cross-reactivity. For some vaccines, this has been substantiated by cross-protection data from clinical studies and/or post-licensure data, where their introduction into immunization programmes has shown beneficial impacts on disease caused by related non-vaccine microorganisms. This knowledge has influenced the way new vaccines are designed, developed, and evaluated in real-life settings. Some of the new vaccines are now designed with the specific aim of having a greater breadth of protection. Ideal vaccine antigens therefore include epitopes with conserved homology across related pathogen types, because it is not always possible to include the antigens of all the individual types of a given pathogen species. The use of novel adjuvants with greater immunostimulatory properties can also contribute to improved overall vaccine cross-reactivity, as could the use of antigen delivery platforms. The growing body of evidence allows us to better understand the full impact of vaccines - beyond vaccine-type disease - which should be taken into consideration when assessing the full value of vaccination programmes.

Stability of an aluminum salt-adjuvanted protein D-conjugated pneumococcal vaccine after exposure to subzero temperatures.

Accidental exposure of a vaccine containing an aluminum-salt adjuvant to temperatures below 0°C in the cold chain can lead to freeze damage. Our study evaluated the potential for freeze damage in a licensed aluminum-salt-containing protein-D-conjugated pneumococcal vaccine (PHiD-CV; Synflorix, GSK) in conditions that included static storage, single subzero-temperature excursions, and simulated air-freight transportation. Several parameters were assessed including freezing at subzero temperatures, aluminum-salt-particle size, antigen integrity and immunogenicity in the mouse. The suitability of the WHO's shake test for identifying freeze-damaged vaccines was also assessed. During subzero-temperature excursions, the mean temperatures at which PHiD-CV froze (-16.7°C to -18.1°C) appeared unaffected by the type of vaccine container (two-dose or four-dose vial, or single-dose syringe), vaccine batch, rotational agitation, or the rate of temperature decline (-0.5 to -10°C/hour). At constant subzero temperature and in simulated air-freight transportation, the freezing of PHiD-CV appeared to be promoted by vibration. At -5°C, no PHiD-CV sample froze in static storage (>1 month), whereas when subjected to vibration, a minority of samples froze (7/21, 33%) within 18 hours. At -8°C with vibration, nearly all (5/6, 83%) samples froze. In these vibration regimes, the shake test identified most samples that froze (10/12, 93%) except two in the -5°C regime. Nevertheless, PHiD-CV-antigen integrity appeared unaffected by freezing up to -20°C or by vibration. And although aluminum-salt-particle size was increased only by freezing at -20°C, PHiD-CV immunogenicity appeared only marginally affected by freezing at -20°C. Therefore, our study supports the use of the shake test to exclude freeze-damaged PHiD-CV in the field.

Public health impact of pneumococcal conjugate vaccine infant immunization programs: assessment of invasive pneumococcal disease burden and serotype distribution.

INTRODUCTION: Pneumococcal conjugate vaccine (PCV) impact studies have reported substantial reductions in the incidence of invasive pneumococcal disease (IPD) after implementation of childhood PCV programs. Heterogeneity in surveillance systems, local epidemiology and PCV programs hampers comparisons between studies. We aimed to better understand the impact of childhood PCV programs on overall IPD and serotype distribution. AREAS COVERED: We analyzed the impact of PCV programs on the incidence of overall IPD, and the distribution of vaccine serotypes (VT) and non-vaccine serotypes (NVT) in children <5 years and adults ≥65 years old. We retrieved datasets from observational post-marketing studies and surveillance reports from countries with high-quality surveillance data available for at least 2 years before PCV program initiation and 3 years after higher-valent PCV implementation. We harmonized pre- and post-PCV analysis periods and assessment methods. EXPERT COMMENTARY: After introduction of pediatric PCV programs, the residual overall IPD burden in children was low and in a narrow range across countries with high vaccination coverage, irrespective of differences in PCV programs and pneumococcal epidemiology. Effects on overall IPD were more variable in the elderly. Whereas IPD was mainly due to VTs before PCV introduction, NVTs are the major contributor today in children and adults.

Impact of pneumococcal conjugate vaccines on otitis media: A review of measurement and interpretation challenges.

Acute otitis media (AOM) is among the most frequent childhood diseases and is caused by various bacterial and viral etiological agents. In this article, we provide an overview of published studies assessing the impact of higher-valent pneumococcal conjugate vaccines (PCVs) on AOM. In some instances, reports of PCV impact on complications of AOM have been included. While randomized controlled trials (RCTs) allow for the most precise assessment of vaccine efficacy against AOM, observational studies provide answers to questions regarding the public health value of these vaccines in real-life settings. We discuss the challenges that arise when measuring PCV impact on AOM in observational studies: the local variability of viral and bacterial etiology, differences in case ascertainment, care-seeking behavior, standards of care and diagnosis of AOM (e.g. use of incisions), as well as declining baseline AOM incidence that can already be in place before PCV introduction, and how these factors can impact the results and their interpretation.

A reflection on invasive pneumococcal disease and pneumococcal conjugate vaccination coverage in children in Southern Europe (2009-2016).

Higher-valent pneumococcal conjugate vaccines (PCVs) were licensed from 2009 in Europe; similar worldwide clinical effectiveness was observed for PCVs in routine use. Despite a proven medical need, PCV vaccination in Southern Europe remained suboptimal until 2015/16. We searched PubMed for manuscripts published between 2009 and mid-2016. Included manuscripts had to contain data about invasive pneumococcal disease (IPD) incidence, or vaccination coverage with higher-valent PCVs. This review represents the first analysis of vaccination coverage and impact of higher-valent PCVs on overall IPD in Southern European countries (Portugal, Spain, Italy, Greece, Cyprus). Vaccination coverage in the Portuguese private market peaked around 2008 at 75% (children ≤ 2 years) but declined to 63% in 2012. In Madrid, coverage was 95% (2007-2012) but dropped to 67% (2013/14; children ≤ 2 years) after funding termination in May 2012. PCVs were recently introduced in the national immunisation program (NIP) of Portugal (2015) and Spain (2015/16). In Italy, coverage for the complete PCV schedule (children ≤ 2 years) was 88% in 2013, although highly variable between regions (45-99%). In Greece, in 2013, 82.3% had received 3 PCV doses by 12 months, while 62.3% received the fourth dose by 24 months. Overall IPD (net benefit: effect on vaccine types, vaccine-related types, and non-vaccine types) has decreased; in Greece, pneumococcal meningitis incidence remained stable. Continued IPD surveillance or national registers using ICD-10 codes of clinically suspected IPD are necessary, with timely publicly available reports and adequate national vaccination registers to assess trends in vaccination coverage, allowing evaluation of PCVs in NIPs.

Response to Wu et al. - Cost-effectiveness analysis of infant pneumococcal vaccination in Malaysia and Hong Kong.

A recently published paper that assessed the comparative cost-effectiveness of the 2 pneumococcal conjugate vaccines (PCVs) in Malaysia and Hong Kong reported that the 13-valent PCV vaccine (PCV13) is a better choice compared to the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV or PCV10) from both a payer and societal perspective as well as under various scenarios. However, the analysis relied on a large number of assumptions that were either erroneous or did not take into account the most recent body of evidence available. A rigorous evaluation of the underlying assumptions is necessary to present a fair and balanced analysis for decision-making.

Impact of the introduction of the pneumococcal conjugate vaccine in the Brazilian routine childhood national immunization program.

Brazil introduced the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix™, GSK Vaccines) in the routine childhood immunization program in 2010 with a 3+1 schedule (with catch-up for children <2 years-old). This review represents the first analysis of the overall impact of a second-generation pneumococcal conjugate vaccine on nasopharyngeal carriage and all the major pneumococcal disease manifestations in a single, pneumococcal conjugate vaccine-naïve, developing country. A total of 15 published articles and 13 congress abstracts were included in the analysis. In children <5 years-old, studies showed a positive impact of PHiD-CV on the incidence of vaccine-type and any-type invasive pneumococcal disease (including decreases in pneumococcal meningitis morbidity and mortality), on pneumonia incidence and mortality, and on otitis media. Nasopharyngeal carriage of vaccine-type and any-type pneumococci decreased after the primary doses, with no early signs of replacement with other pathogens. Finally, herd protection against vaccine-type invasive pneumococcal disease and pneumonia in unvaccinated subjects was shown in some studies for some age groups. In conclusion, pneumococcal disease decreased after the introduction of PHiD-CV into the Brazilian national immunization program. Further follow-up is needed to evaluate the long-term overall impact of PHiD-CV in the Brazilian population.

Further available immunization option to prevent pneumococcal disease.

In their recent review, Charles Feldman and Ronald Anderson provide an overview of various clinical aspects of pneumococcal infections. We would like to complete this report by providing some additional information on a widely-used immunization option, which was not originally mentioned in the article. The protein D pneumococcal conjugate vaccine (PHiD-CV) has been pre-approved by WHO and its impact is supported by real-life data from the regions of its use.