ACIP recommendations for COVID-19 vaccines-and more.

Prioritized immunization is advised with the 2 COVID-19 vaccines. A third meningococcal ACWY vaccine is now the only one approved for those > 55 years.

BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of health care workers.

BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune-boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODSWe assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTSOf the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONSA history of BCG vaccination was associated with a decrease in the seroprevalence of anti-SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection.

Immunogenicity and Safety of a Two-Dose Series of a Meningococcal (Groups A, C, W, and Y) Polysaccharide Diphtheria Toxoid Conjugate Vaccine (Men-ACWY-D) in Healthy Japanese Adults.

The quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (Men-ACWY-D) has been licensed for use in Japan since 2014. An earlier registration study demonstrated the immunogenicity of a single dose in Japanese adults, wherein the immunogenicity against serogroup C was the lowest. The determination of the potential to increase the serogroup C response with a second dose was, therefore, of interest. This study (NCT02591290) evaluated the safety and immunogenicity of two doses administered 8 weeks apart to 60 healthy Japanese adults aged 20-55 years. Blood samples were collected at 28-35 days after vaccination. Immunogenicity endpoints included seroprotection and seroconversion rates. Safety assessments included systemic adverse events (AEs), non-serious AEs, and serious AEs. Fifty-eight participants (96.7%) completed the study. The seroprotection rates for serogroups A, C, W, and Y before vaccination were 76.8%, 26.8%, 26.8%, and 50.0%, respectively, increasing to 100%, 83.9%, 91.1%, and 96.4% and 100%, 92.9%, 94.6%, and 94.6%, respectively, after two doses. The seroconversion rates for the four serogroups were 100%, 93.8%, 97.1%, and 94.1%, respectively, after the first dose, and 100%, 96.9%, 100%, and 100%, respectively, after the second. The increase between the doses was insignificant, and there were no safety concerns. The two-dose series was well tolerated; however, the clinical benefits of a second dose within 8 weeks seemed to be low.

The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae.

There is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. Serum IgG and vaginal IgA and IgG that cross-reacted with Ng OMVs were induced by 4CMenB vaccination by either the subcutaneous or intraperitoneal routes. Antibodies from vaccinated mice recognized several Ng surface proteins, including PilQ, BamA, MtrE, NHBA (known to be recognized by humans), PorB, and Opa. Immune sera from both mice and humans recognized Ng PilQ and several proteins of similar apparent molecular weight, but MtrE was only recognized by mouse serum. Pooled sera from 4CMenB-immunized mice showed a 4-fold increase in serum bactericidal50 titers against the challenge strain; in contrast, no significant difference in bactericidal activity was detected when sera from 4CMenB-immunized and unimmunized subjects were compared. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against gonorrhea, and implicate several Ng surface antigens as potentially protective targets. Additionally, this study further defines the usefulness of murine infection model as a relevant experimental system for gonorrhea vaccine development.

Low efficacy of vaccination against serogroup B meningococci in patients with atypical hemolytic uremic syndrome.

BACKGROUND: The C5 complement inhibitor eculizumab is first-line treatment in atypical hemolytic uremic syndrome (aHUS) going along with a highly increased risk of meningococcal infections. Serogroup B meningococci (MenB) are the most frequently encountered cause for meningococcal infections in Europe. Efficacy of the protein-based MenB-vaccine Bexsero in aHUS has not been determined and testing is only possible in patients off-treatment with eculizumab as a human complement source is required. METHODS: Patients with aHUS were vaccinated with two doses of the protein-based MenB-vaccine Bexsero. Serum bactericidal antibody (SBA) titers against factor H binding protein (fHbp) of MenB were determined in 14 patients with aHUS off-treatment with eculizumab. RESULTS: Only 50% of patients showed protective human serum bactericidal antibody (hSBA) titers (≥1:4) against MenB following two vaccinations. Bactericidal antibody titers were relatively low (≤1:8) in three of seven patients with protective titers. While 71% of patients were on immunosuppressive treatment for either thrombotic microangiopathy or renal transplantation at either first or second vaccination, all four patients not receiving any immunosuppressive treatment showed protective bactericidal antibody response. Time between second vaccination and titer measurement was not significantly different between patients with protective titers compared with those with non-protective titers, while time between first and second vaccination was significantly longer in patients with protective titers going along with a tendency for reduction in immunosuppressive treatment. CONCLUSIONS: Efficacy of vaccination against MenB is insufficient in patients with aHUS. Response to vaccination seems to be hampered by immunosuppression. Therefore, implementation of adequate antibiotic prophylaxis seems pivotal.

A preliminary study on the application of PspA as a carrier for group A meningococcal polysaccharide.

This study aimed to explore the feasibility of pneumococcal surface protein A (PspA) as a carrier protein. Three recombinant pneumococcal surface proteins from three different clades were expressed by the prokaryotic expression system and conjugated to group A meningococcal polysaccharide (GAMP) to generate three polysaccharide-protein conjugates. The conjugates, unconjugated proteins, GAMP, and GAMP-TT vaccine bulk (used as positive control) were immunized into mice, and their immune effects were assessed by the methods of enzyme-linked immunosorbent assay (ELISA), flow cytometry (FCM), and serum bactericidal assay (SBA). The results showed that the polysaccharide-protein conjugates could produce higher levels of anti-GAMP IgG titers (P < 0.05), higher ratios of Th1/Th2 (P < 0.05), and higher levels of serum bactericidal activity (P < 0.05), compared with the unconjugated GAMP. The conjugation of PspAs to GAMP also enhanced the anti-PspA responses compared with unconjugated PspAs except for PspA3. In conclusion, the results indicated that the three PspAs were appropriate carrier proteins, as demonstrated by the characteristics of T-cell dependent responses to the GAMP, and might protect against group A of epidemic cerebrospinal meningitis.

Polysaccharide structure dictates mechanism of adaptive immune response to glycoconjugate vaccines.

Glycoconjugate vaccines are among the most effective interventions for preventing several serious infectious diseases. Covalent linkage of the bacterial capsular polysaccharide to a carrier protein provides CD4+ T cells with epitopes that facilitate a memory response to the polysaccharide. Classically, the mechanism responsible for antigen processing was thought to be similar to what was known for hapten-carrier conjugates: protease digestion of the carrier protein in the endosome and presentation of a resulting peptide to the T cell receptor on classical peptide-recognizing CD4+ T cells. Recently, an alternative mechanism has been shown to be responsible for the memory response to some glycoconjugates. Processing of both the protein and the polysaccharide creates glycopeptides in the endosome of antigen-presenting cells. For presentation, the peptide portion of the glycopeptide is bound to MHCII, allowing the covalently linked glycan to activate carbohydrate-specific helper CD4+ T cells (Tcarbs). Herein, we assessed whether this same mechanism applies to conjugates prepared from other capsular polysaccharides. All of the glycoconjugates tested induced Tcarb-dependent responses except that made with group C Neisseria meningitidis; in the latter case, only peptides generated from the carrier protein were critical for helper T cell recognition. Digestion of this acid-sensitive polysaccharide, a linear homopolymer of α(2 → 9)-linked sialic acid, to the size of the monomeric unit resulted in a dominant CD4+ T cell response to peptides in the context of MHCII. Our results show that different mechanisms of presentation, based on the structure of the carbohydrate, are operative in response to different glycoconjugate vaccines.

A new meningococcal B vaccine for adolescents and adults: characteristics and methods of use.

The invasive disease from Neisseria meningitidis is one of the leading causes of death for meningitis and sepsis at all ages. The highest incidence of cases occurs at paediatric and adolescent age, but no age of life is considered protected from this infection and disease. Prevention against the five main serogroups is possible using the combined conjugated polysaccharide vaccine against the ACWY (anti-MenACWY) serogroups and the meningococcal B (anti-MenB) protein vaccines. Trumenba® vaccine, approved by the EMA (European Medicine Agency) for use in individuals aged ≥ 10 years, protects against serogroup B invasive disease. This bivalent, recombinant vaccine is able, when given with a 0-6 month schedule, to induce a protective response in adolescents and young adults, comparable with a 3-doses schedule. For this reason, the Trumenba® vaccine should be used routinely with the 2-dose schedule (0-6 months). The 3-doses use could be considered in particular situations, like an occurring epidemic or particular individual risk factors such as asplenia or complement deficit, but is not needed for underlying conditions like diabetes or heart diseases.

UK parents' attitudes towards meningococcal group B (MenB) vaccination: a qualitative analysis.

OBJECTIVES: (1) To explore existing knowledge of, and attitudes, to group B meningococcal disease and serogroup B meningococcal (MenB) vaccine among parents of young children. (2) To seek views on their information needs. DESIGN: Cross-sectional qualitative study using individual and group interviews conducted in February and March 2015, prior to the introduction of MenB vaccine (Bexsero) into the UK childhood immunisation schedule. SETTING: Community centres, mother and toddler groups, parents' homes and workplaces in London and Yorkshire. PARTICIPANTS: 60 parents of children under 2 years of age recruited via mother and baby groups and via an advert posted to a midwife-led Facebook group. RESULTS: Although recognising the severity of meningitis and septicaemia, parents' knowledge of group B meningococcal disease and MenB vaccine was poor. While nervous about fever, most said they would take their child for MenB vaccination despite its link to fever. Most parents had liquid paracetamol at home. Many were willing to administer it after MenB vaccination as a preventive measure, although some had concerns. There were mixed views on the acceptability of four vaccinations at the 12-month booster visit; some preferred one visit, while others favoured spreading the vaccines over two visits. Parents were clear on the information they required before attending the immunisation appointment. CONCLUSIONS: The successful implementation of the MenB vaccination programme depends on its acceptance by parents. In view of parents' recognition of the severity of meningitis and septicaemia, and successful introduction of other vaccines to prevent bacterial meningitis and septicaemia, the MenB vaccination programme is likely to be successful. However, the need for additional injections, the likelihood of post-immunisation fever and its management are issues about which parents will need information and reassurance from healthcare professionals. Public Health England has developed written information for parents, informed by these findings.

Rapid response to a college outbreak of meningococcal serogroup B disease: Nation's first widespread use of bivalent rLP2086 vaccine.

OBJECTIVE: To outline the reasoning behind use of bivalent rLP2086 in a Rhode Island college meningococcal B disease outbreak, highlighting the timeline from outbreak declaration to vaccination clinic, emphasizing that these two time points are <3 days apart. PARTICIPANTS: Staff, faculty, and students at College X eligible for vaccination. METHODS: An outbreak response was initiated, advantages/disadvantages of available MenB vaccines were discussed, and a vaccination clinic was coordinated. RESULTS: Bivalent rLP2086 was chosen as the vaccination intervention. We achieved a 94% coverage rate for the first dose. To date, this intervention has prevented further cases of Neisseria meningitidis serogroup B disease at College X. CONCLUSIONS: The close, efficient collaboration of public health stakeholders and College X led 94% of the eligible population to be safely vaccinated with at least one dose of bivalent rLP2086. This outbreak marked the first time bivalent rLP2086 was effectively used as an intervention response.

[Bexsero, a novel vaccine against meningococcus]. / Bexsero, egy új, meningococcus elleni vakcina.

Meningococcus B is the most prevalent Neisseria meningitidis serogroup isolated in Hungary. Bexsero is one of the vaccines developed against it, which has been available in Hungary since the summer of 2014. The authors summarize the most important issues and open questions concerning the disease and the vaccine based on literature review. Based on immunological evidence, it is expected that Bexsero provides protection against this rare but very serious infection. However, the vaccine is extremely expensive, the clinical effectiveness has not yet been proven and it frequently causes fever, especially in infants where the vaccine is most needed. According to the opinion of the authors, the formulation of a Hungarian guideline concerning the application of Bexsero should be postponed until the accumulating international experience makes it possible to better judge the vaccine's benefits, risks and cost-effectiveness. For patients with asplenia, complement defect or other immunological defect, or in case of markedly increased individual risk of contracting the disease, the vaccination is already justified.

Vaccines for Prevention of Group B Meningococcal Disease: Not Your Father's Vaccines.

For decades, there was no licensed vaccine for prevention of endemic capsular group B meningococcal disease, despite the availability of vaccines for prevention of the other most common meningococcal capsular groups. Recently, however, two new vaccines have been licensed for prevention of group B disease. Although immunogenic and considered to have an acceptable safety profile, there are many scientific unknowns about these vaccines, including effectiveness against antigenically diverse endemic meningococcal strains; duration of protection; whether they provide any herd protection; and whether there will be meningococcal antigenic changes that will diminish effectiveness over time. In addition, these vaccines present societal dilemmas that could influence how they are used in the U.S., including high vaccine cost in the face of a historically low incidence of meningococcal disease. These issues are discussed in this review.

Synthesis and immunological study of α-2,9-oligosialic acid conjugates as anti-group C meningitis vaccines.

α-2,9-Di-, tri-, tetra-, and pentasialic acids were prepared and conjugated with a carrier protein. The resultant glycoconjugates elicited robust T cell-mediated immunity in mice. α-2,9-Trisialic acid was identified as a promising antigen for developing glycoconjugate vaccines against group C Neisseria meningitidis.

Induction of death receptor CD95 and co-stimulatory molecules CD80 and CD86 by meningococcal capsular polysaccharide-loaded vaccine nanoparticles.

Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis, and its capsular polysaccharides (CPS) are a major virulence factor in meningococcal infections and form the basis for serogroup designation and protective vaccines. We formulated a novel nanovaccine containing meningococcal CPS as an antigen encapsulated in albumin-based nanoparticles (NPs) that does not require chemical conjugation to a protein carrier. These nanoparticles are taken up by antigen-presenting cells and act as antigen depot by slowly releasing the antigen. In this study, we determined the ability of CPS-loaded vaccine nanoparticles to induce co-stimulatory molecules, namely CD80, CD86, and CD95 that impact effective antigen presentation. Co-stimulatory molecule gene induction and surface expression on macrophages and dendritic cells pulsed with meningococcal CPS-loaded nanoparticles were investigated using gene array and flow cytometry methods. Meningococcal CPS-loaded NP significantly induced the surface protein expression of CD80 and CD86, markers of dendritic cell maturation, in human THP-1 macrophages and in murine dendritic cells DC2.4 in a dose-dependent manner. The massive upregulation was also observed at the gene expression. However, high dose of CPS-loaded NP, but not empty NP, induced the expression of death receptor CD95 (Fas) leading to reduced TNF-α release and reduction in cell viability. The data suggest that high expression of CD95 may lead to death of antigen-presenting cells and consequently suboptimal immune responses to vaccine. The CPS-loaded NP induces the expression of co-stimulatory molecules and acts as antigen depot and can spare antigen dose, highly desirable criteria for vaccine formulations.

Combined meningococcal serogroup A and W135 outer-membrane vesicles activate cell-mediated immunity and long-term memory responses against non-covalent capsular polysaccharide A.

Outer-membrane vesicles (OMVs) have inherent adjuvant properties, and many vaccines use OMV as vaccine components. Utilizing the adjuvant properties of OMV could lead to the formulation of vaccines that are less expensive and potentially more immunogenic than covalently conjugated polysaccharide vaccines. We evaluated the adjuvant effect in Balb/c mice of combinations of OMV from Neisseria meningitidis serogroup A and W135 as compared to that of the non-covalently conjugated capsular polysaccharide A. Both antigens were adsorbed onto aluminum hydroxide. The mice were given a booster dose of plain polysaccharide A to stimulate an immunologic memory response. Subclasses determination and cytokine assays demonstrated the capacity of OMV to induce a IgG2a/IgG2b isotype profile and IFN-γ production, suggesting the induction of a Th1 pattern immune response. Lymphoproliferative responses to OMVs were high, with affinity maturation of antibodies observed. Bactericidal titers after the booster dose were also observed. Memory B cells and long-term memory T cells were also detected. The results of this study indicate that combined meningococcal serogroup A and W135 OMV can activate cell-mediated immunity and induce a long-term memory response.

MenHibrix: a new combination meningococcal vaccine for infants and toddlers.

OBJECTIVE: To review the immunogenicity and safety of the Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine (Hib-MenCY-TT) for infants and toddlers. DATA SOURCES: Studies conducted in humans and limited to publication in English were identified through a MEDLINE (January 2000 to September 2013) search using the terms Hib-MenCY-TT, MenHibrix, and Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine. Clinical trial registries, Web sites, and reference citations from publications identified were reviewed for additional sources. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials were included to evaluate the safety and immunogenicity of Hib-MenCY-TT. Epidemiological data and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed. DATA SYNTHESIS: Hib-MenCY-TT is available for primary vaccination of infants as a 4-dose series at 2, 4, 6, and 12 to 15 months of age. Hib-MenCY-TT has comparable immunogenicity to licensed Hib vaccines and produces high levels of N meningitidis antibodies against serogroups C and Y. The most common adverse events were pain and redness at the injection site, drowsiness, and irritability. CONCLUSIONS: Hib-MenCY-TT has been demonstrated to be a safe and immunogenic vaccination for prevention of disease caused by N meningitidis serogroups C and Y and H influenzae type b in healthy infants and toddlers. Currently, the ACIP recommends the use of Hib-MenCY-TT specifically in high-risk infants aged 6 weeks to 18 months. Hib-MenCY-TT provides the first therapeutic option for vaccination of infants as young as 6 weeks of age who are at increased risk for meningococcal disease.

On the trail of preventing meningococcal disease: a survey of students planning to travel to the United States.

BACKGROUND: College freshmen living in dormitories are at increased risk for meningococcal disease. Many students become a high-risk population when they travel to the United States. This study surveyed the knowledge, attitudes toward, and behavior surrounding the disease among Taiwanese college students planning to study in the United States, and to identify factors that may affect willingness to accept meningococcal vaccination. METHODS: A cross-sectional survey of college students going to study in the United States was conducted in a medical center-based travel medicine clinic. Background information, attitudes, general knowledge, preventive or postexposure management, and individual preventive practices were collected through a structured questionnaire. RESULTS: A total of 358 students were included in the final analysis. More than 90% of participants believed that preventing meningococcal disease was important. However, fewer than 50% of students accurately answered six of nine questions exploring knowledge of the disease, and only 17.3% of students knew the correct management strategy after close contact with patients. Logistic regression analysis showed that students who understood the mode of transmission (odds ratio: 3.21, 95% CI = 1.117-9.229), medication management (1.88, 1.045-3.38), and epidemiology (2.735, 1.478-5.061) tended to be vaccinated. CONCLUSIONS: Despite an overall positive attitude toward meningococcal vaccination, there was poor knowledge about meningococcal disease. Promoting education on the mode of transmission, epidemiology, and pharmacological management of the disease could increase vaccination rates. Both the governments and travel medicine specialists should work together on developing an education program for this high-risk group other than just requiring vaccination.

Immunization with recombinant Chaperonin60 (Chp60) outer membrane protein induces a bactericidal antibody response against Neisseria meningitidis.

Sera from individuals colonized with Neisseria meningitidis and from patients with meningococcal disease contain antibodies specific for the neisserial heat-shock/chaperonin (Chp)60 protein. In this study, immunization of mice with recombinant (r)Chp60 in saline; adsorbed to aluminium hydroxide; in liposomes and detergent micelles, with and without the adjuvant MonoPhosphoryl Lipid A (MPLA), induced high and similar (p>0.05) levels of antibodies that recognized Chp60 in outer membranes (OM). FACS analysis and immuno-fluorescence experiments demonstrated that Chp60 was surface-expressed on meningococci. By western blotting, murine anti-rChp60 sera recognized a protein of Mr 60kDa in meningococcal cell lysates. However, cross-reactivity with human HSP60 protein was also observed. By comparing translated protein sequences of strains, 40 different alleles were found in meningococci in the Bacterial Isolate Genome Sequence database with an additional 5 new alleles found in our selection of 13 other strains from colonized individuals and patients. Comparison of the non-redundant translated amino acid sequences from all the strains revealed ≥97% identity between meningococcal Chp60 proteins, and in our 13 strains the protein was expressed to high and similar levels. Bactericidal antibodies (median reciprocal titres of 32-64) against the homologous strain MC58 were induced by immunization with rChp60 in liposomes, detergent micelles and on Al(OH)3. Bactericidal activity was influenced by the addition of MPLA and the delivery formulation used. Moreover, the biological activity of anti-Chp60 antisera did not extend significantly to heterologous meningococcal strains. Thus, in order to provide broad coverage, vaccines based on Chp60 would require multiple proteins and specific bactericidal epitope identification.

Quantitative proteomics reveals distinct differences in the protein content of outer membrane vesicle vaccines.

At present, only vaccines containing outer membrane vesicles (OMV) have successfully stopped Neisseria meningitidis serogroup B epidemics. These vaccines however require detergent-extraction to remove endotoxin, which changes immunogenicity and causes production difficulties. To investigate this in more detail, the protein content of detergent-extracted OMV is compared with two detergent-free alternatives. A novel proteomics strategy has been developed that allows quantitative analysis of many biological replicates despite inherent multiplex restrictions of dimethyl labeling. This enables robust statistical analysis of relative protein abundance. The comparison with detergent-extracted OMV reveales that detergent-free OMV are enriched with membrane (lipo)proteins and contain less cytoplasmic proteins due to a milder purification process. These distinct protein profiles are substantiated with serum blot proteomics, confirming enrichment with immunogenic proteins in both detergent-free alternatives. Therefore, the immunogenic protein content of OMV vaccines depends at least partially on the purification process. This study demonstrates that detergent-free OMV have a preferred composition.