Unveiling the contributions of immunization for progressing towards Universal Health Coverage.

The aim of the United Nations' Sustainable Development Goal (SDG)3 is to ensure healthy lives and promote well-being for all, at all ages; including reducing maternal and child mortality, combating communicable and non-communicable diseases, and achieving Universal Health Coverage (UHC). UHC aims to provide everyone with equal access to quality essential and comprehensive healthcare services including preventions, interventions, and treatments, without exposing them to financial hardship. Making progress toward UHC requires significant investment in technical and financial resources and countries are pursuing the implementation of cost-saving measures within health systems to help them achieve UHC. Whilst many countries are far from attaining UHC, all countries, particularly low- and middle-income countries, can take steps toward achieving UHC. This paper discusses key data showing how immunization is a fundamental, cost-effective tool for reducing morbidity and mortality associated with infectious disease in all populations, creating more productive communities, reducing treatment costs, and consequently, facilitating social and economic advancement. Immunization is key to advancing toward UHC by relieving the burden that diseases place on the healthcare services, freeing essential resources to use elsewhere within the healthcare system. Immunization is an essential, readily available strategy that countries can deploy to achieve UHC and the SDG3 agenda.

Evolving measles status and immunization policy development in six European countries.

Developing and implementing new immunization policies in response to shifting epidemiology is a critical public health component. We adopted a mixed-methods approach (via narrative literature review [101 articles] and 9 semi-structured interviews) to evaluate policy development in response to shifting measles epidemiology in six European countries (Italy, Belgium, Germany, Romania, UK, and Ukraine); where policies and strategies have evolved in response to country-specific disease and vaccination patterns. Periodic outbreaks have occurred in all countries against a background of declining measles-containing-vaccine (MCV) uptake and increasing public vaccine hesitancy (with substantial regional or social differences in measles burden and vaccine uptake). Health-care worker (HCW) vaccine skepticism is also seen. While many outbreaks arise or involve specific susceptible populations (e.g., minority/migrant communities), the broader pattern is spread to the wider (and generally older) population; often among incompletely/non-vaccinated individuals as a legacy of previous low uptake. Immunization policy and strategic responses are influenced by political and social factors, where public mistrust contributes to vaccine hesitancy. A strong centralized immunization framework (allied with effective regional implementation and coherent political commitment) can effectively increase uptake. Mandatory vaccination has increased childhood MCV uptake in Italy, and similar benefits could be anticipated for other countries considering vaccine mandates. Although possible elsewhere, socio-political considerations render mandating impractical in other countries, where targeted immunization activities to bolster routine uptake are more important. Addressing HCW skepticism, knowledge gaps, improving access and increasing public/community engagement and education to address vaccine hesitancy/mistrust (especially in communities with specific unmet needs) is critical.

The intent of students to vaccinate is influenced by cultural factors, peer network, and knowledge about vaccines.

Young adults are the future vaccine decision-makers as parents or health-care professionals. To understand their attitudes and behaviors toward vaccination, we conducted a cross-sectional survey of 2079 students attending the University of Antwerp, Belgium and the University of Pisa, Italy. Principal component analysis was used to investigate associations between survey responses and the intent to vaccinate. Vaccination knowledge, attitudes, and behaviors among university students in Italy and Belgium were high. However, only one-half of respondents displayed an intent to vaccinate. High levels of knowledge, positive attitudes, and confidence in vaccines were positively associated with age, higher level of study, being a medical student, a recent vaccination experience, and not knowing trusted persons who did not believe in vaccines. Country of origin was highly correlated with the survey responses and was clustered with lifestyle, family, and data source variables, suggesting a strong modifying effect of culture and family attitudes on how vaccines are perceived in this age-group. Recent meningococcal vaccination campaigns and public discussions around mandatory vaccination in Italy may have influenced these results. We show that the intent to vaccinate was correlated with two main clusters of variables linked to culture (country, family, lifestyle), and to scholarship (knowledge, attitudes, data source) that together influence the behavior of students with respect to vaccination. Our study reinforces previous findings that knowledge about vaccines is key to shaping attitudes and behaviors, but also shows that cultural and lifestyle factors are another platform that could be leveraged in promoting vaccination among young people.

CIRCULATING CLONAL COMPLEXES AND SEQUENCE TYPES OF STREPTOCOCCUS PNEUMONIAE SEROTYPE 19A WORLDWIDE: THE IMPORTANCE OF MULTIDRUG RESISTANCE: A SYSTEMATIC LITERATURE REVIEW.

INTRODUCTION: Streptococcus pneumoniae is a major cause of morbidity and mortality, especially amongst young children and the elderly. Childhood implementation of pneumococcal conjugate vaccines (PCVs) significantly reduced the incidence of invasive pneumococcal disease (IPD), while several nonvaccine serotypes remained substantial. Although there is evidence of the impact of higher-valent PCVs on serotype 19A, 19A IPD burden and antibiotic resistance remain a major concern post-vaccination. AREAS COVERED: We performed a systematic literature review to analyze the frequency and clonal distribution of serotype 19A isolates in the pre- and post-PCV era worldwide providing a scientific background on the factors that influence multidrug resistance in pneumococcal isolates. EXPERT COMMENTARY: Serotype 19A IPD incidence increased in all regions following the introduction of the 7-valent PCV. The higher-valent PCVs have reduced the rates of 19A IPD isolates, but several circulating strains with diverse antibiotic resistance prevailed. Heterogeneous clonal distribution in serotype 19A was observed within countries and regions, irrespective of higher-valent PCV used. An increase of 19A isolates from pre- to post-vaccination periods were associated with frequently occurring serotype switching events and with the prevalence of multidrug resistant strains. Rational antibiotic policies must be implemented to control the emergence of resistance.Plain Language SummaryWhat is the context?Streptococcus pneumoniae is a major cause of pneumococcal diseases especially amongst young children and the elderly. Vaccination with pneumococcal conjugate vaccines has significantly reduced the incidence of invasive pneumococcal disease worldwide. However, the invasive pneumococcal disease remains an important health problem due to the increase of nonvaccine serotypes. Serotype 19A is predominant in many countries worldwide. Factors contributing to its prevalence include serotype replacement, the emergence of clones with multidrug resistance due to antibiotic overuse, and potential bacteria adaptation in response to the vaccine.What is new?We performed a systematic literature review to 1) analyze the incidence and clonal distribution of serotype 19A isolates pre- and post-vaccination worldwide, and to collect data evaluating antimicrobial resistance patterns displayed by the clones of serotype 19A. We found that 1) clonal distribution in serotype 19A was heterogeneous within countries and regions, irrespective of the vaccine used; 2) the diversity of 19A isolates increased after vaccination. It was associated with frequent serotype switching events and with the prevalence of multidrug resistant strains.What is the impact?Implementation of policies to educate on sustainable antibiotic use and infectious prevention measures may help control the emergence of antibiotic resistance. High-quality active surveillance and future molecular epidemiology studies are needed to understand rapid genetic changes.

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.

Maternal immunization: where are we now and how to move forward?

Pregnancy and the postpartum period are associated with elevated risks to both mother and infant from infectious disease. Vaccination of pregnant women, also called maternal immunization, has the potential to protect pregnant women, foetuses and infants from several vaccine-preventable diseases. Maternal immunoglobulin G antibodies are actively transferred through the placenta to provide passive immunity to new-borns during the first months of life, until the time for infant vaccinations or until the period of greatest susceptibility has passed. Currently, inactivated influenza, tetanus, and pertussis vaccines are recommended during pregnancy in many countries, but other vaccines may also be administered to pregnant women when risk factors are present. Several new vaccines with a specific indication for use during pregnancy are under development (e.g. respiratory syncytial virus and group B streptococcus vaccines). Years of experience suggest that maternal immunization against influenza, tetanus or pertussis has an acceptable safety profile, is well tolerated, effective and confers significant benefits to pregnant women and their infants. This review describes the principles of maternal immunization and provides an update of the recent evidence regarding the use and timing of maternal immunization. Finally, the barriers preventing wider vaccination coverage and the current limitations in addressing these are also described ( Supplementary Material ). Key messages Maternal immunization gives pregnant women greater protection against infectious diseases; induces high levels of maternal antibodies that can be transferred to the foetus; and helps protect new-borns during their first months of life, until they are old enough to be vaccinated. Pregnant women and new-borns are more vulnerable to infectious diseases than the overall population; nevertheless, vaccination rates are often low in pregnant women. This review provides an update of the recent evidence regarding the use and timing of maternal immunization and describes the barriers preventing wider vaccination uptake and the current limitations in addressing these.

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.

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.

Polysaccharide conjugate vaccine protein carriers as a "neglected valency" - Potential and limitations.

The development of vaccines against polysaccharide-encapsulated pathogens (e.g. Haemophilus influenzae type b, pneumococci, meningococci) is challenging because polysaccharides do not elicit a strong and long-lasting immune response (i.e. T-cell independent). This can be overcome by conjugating the polysaccharide to a protein carrier (e.g. tetanus toxoid, cross-reacting material 197 [CRM]), which vastly improves the immune response and induces memory to the polysaccharide (T-cell dependent). Although it is well documented that protein carriers additionally induce an immune response against themselves, this potential "additional valency" has so far not been recognized. The only exception is for the protein D carrier (derived from non-typeable Haemophilus influenzae [NTHi]) used in a pneumococcal conjugate vaccine, which may have a beneficial impact on NTHi acute otitis media. In this review, we describe the immunogenicity of various protein carriers and discuss their potential dual function: as providers of T-cell helper epitopes and as protective antigens. If this "additional valency" could be proven to be protective, it may be possible to consider its potential effect on the number of required immunizations. We also describe the potential for positive or negative interference between conjugate vaccines using the same protein carriers, the resulting desire for novel carriers, and information on potential new carriers. The range of conjugate vaccines is ever expanding, with different carriers and methods of conjugation. We propose that new conjugate vaccine trials should assess immunogenicity to both the polysaccharide and carrier. Ultimately, this so-far "neglected valency" could be an exploitable characteristic of polysaccharide conjugate vaccines.

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.

Group A streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9.

Bacterial pathogens are recognized by the innate immune system through pattern recognition receptors, such as Toll-like receptors (TLRs). Engagement of TLRs triggers signaling cascades that launch innate immune responses. Activation of MAPKs and NF-kappaB, elements of the major signaling pathways induced by TLRs, depends in most cases on the adaptor molecule MyD88. In addition, Gram-negative or intracellular bacteria elicit MyD88-independent signaling that results in production of type I interferon (IFN). Here we show that in mouse macrophages, the activation of MyD88-dependent signaling by the extracellular Gram-positive human pathogen group A streptococcus (GAS; Streptococcus pyogenes) does not require TLR2, a receptor implicated in sensing of Gram-positive bacteria, or TLR4 and TLR9. Redundant engagement of either of these TLR molecules was excluded by using TLR2/4/9 triple-deficient macrophages. We further demonstrate that infection of macrophages by GAS causes IRF3 (interferon-regulatory factor 3)-dependent, MyD88-independent production of IFN. Surprisingly, IFN is induced also by GAS lacking slo and sagA, the genes encoding cytolysins that were shown to be required for IFN production in response to other Gram-positive bacteria. Our data indicate that (i) GAS is recognized by a MyD88-dependent receptor other than any of those typically used by bacteria, and (ii) GAS as well as GAS mutants lacking cytolysin genes induce type I IFN production by similar mechanisms as bacteria requiring cytoplasmic escape and the function of cytolysins.

Lysogenic transfer of group A Streptococcus superantigen gene among Streptococci.

A group A Streptococcus (GAS) isolate, serotype M12, recovered from a patient with streptococcal toxic shock syndrome was analyzed for superantigen-carrying prophages, revealing phi149, which encodes superantigen SSA. Sequence analysis of the att-L proximal region of phi149 showed that the phage had a mosaic nature. Remarkably, we successfully obtained lysogenic conversion of GAS clinical isolates of various M serotypes (M1, M3, M5, M12, M19, M28, and M94), as well as of group C Streptococcus equisimilis (GCSE) clinical isolates, via transfer of a recombinant phage phi149::Km(r). Phage phi149::Km(r) from selected lysogenized GAS and GCSE strains could be transferred back to M12 GAS strains. Our data indicate that horizontal transfer of lysogenic phages among GAS can occur across the M-type barrier; these data also provide further support for the hypothesis that toxigenic conversion can occur via lysogeny between species. Streptococci might employ this mechanism specifically to allow more efficient adaptation to changing host challenges, potentially leading to fitter and more virulent clones.