Preclinical evaluation of an investigational 21-valent pneumococcal conjugate vaccine,V116, in adult-rhesus monkey,rabbit, and mouse models

Despite the widespread effectiveness of pneumococcal conjugate vaccines on the overall incidence of invasive pneumococcal disease, the global epidemiological landscape continues to be transformed by residual disease from non-vaccine serotypes, thus highlighting the need for vaccines with expanded disease coverage. To address these needs, we have developed V116, an investigational 21-valent non-adjuvanted pneumococcal conjugate vaccine (PCV), containing pneumococcal polysaccharides (PnPs) 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B, and a de-O-acetylated 15B (deOAc15B) individually conjugated to the nontoxic diphtheria toxoid CRM197 carrier protein. Preclinical studies evaluated the immunogenicity of V116 in adult monkeys, rabbits, and mice. Following one dose, V116 was found to be immunogenic in preclinical animal species and induced functional antibodies for all serotypes included in the vaccine, in addition to cross-reactive functional antibodies to serotypes 6C and 15B. In these preclinical animal studies, the increased valency of V116 did not result in serotype-specific antibody suppression when compared to lower valent vaccines V114 or PCV13. In addition, when compared with naïve controls, splenocytes from V116 to immunized animals demonstrated significant induction of CRM197-specific T cells in both IFN-γ and IL-4 ELISPOT assays, as well as Th1 and Th2 cytokine induction through in vitro stimulation assays, thus suggesting the ability of V116 to engage T cell dependent immune response pathways to aid in development of memory B cells. V116 also demonstrated significant protection in mice from intratracheal challenge with serotype 24F, a novel serotype not contained in any currently licensed vaccine.     

Immunogenicity of PCV24, an expanded pneumococcal conjugate vaccine,in adult monkeys and protection in mice

Invasive pneumococcal disease (IPD) is responsible for serious illnesses such as bacteremia, sepsis, meningitis, and pneumonia in young children, older adults, and persons with immunocompromising conditions and often leads to death. Although the most recent pneumococcal conjugate vaccines (PCVs) have been designed to target serotypes identified as the primary causative agents of IPD, the epidemiological landscape continues to change stressing the need to develop new PCVs. We have developed an investigational 24-valent PCV (PCV24) including serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F all conjugated to CRM197 and evaluated this vaccine in adult monkeys. PCV24 was shown to be immunogenic and induced functional antibody for all vaccine serotypes. Of the serotypes common to PCV13 and V114 (PCV15), PCV24 had a similar immunogenic response with the exceptions of 23F which had higher IgG GMCs for PCV13 and V114, and 7F which had higher GMCs for PCV13. Functional antibody responses were similar for the serotypes in common between PCV24, PCV13 and V114 vaccines, with the exception of serotype 7F which was greater for PCV13. Overall, this study shows that PCV24 provided similar immunogenicity as the lower valent vaccines in adult monkeys with no apparent serotype interference. In addition, PCV24 also provided protection against pneumococcal infection in a mouse challenge model.     

Assignment of opsonic values to pneumococcal reference serum 007sp and a second pneumococcal OPA calibration serum panel (Ewha QC sera panel B) for 11 serotypes

Pneumococcal conjugate vaccines (PCVs) have been effective in reducing the disease burden caused by Streptococcus pneumoniae. The first licensed PCV (PCV7) was composed of capsular polysaccharides from seven serotypes. This was followed by PCV10, then PCV13, and currently there are a number of higher valency vaccines in development. As part of licensure, new vaccine iterations require assessment of immunogenicity. Since some antibodies can be non-functional, measuring functional antibodies is desirable. To meet this need, opsonophagocytic assays (OPAs) have been developed. Previous studies have shown there can be significant variations in OPA results from different laboratories. We have previously shown that standardizing OPA data using reference serum 007sp can decrease this variation.To extend this approach to additional serotypes, a panel of sera was tested by five laboratories using a multiplexed OPA for serotypes 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, and 33F. Each sample was tested in five runs with 007sp tested three times in each run. Results were analyzed using a mixed effects ANOVA model.Standardization of the results significantly decreased the inter-laboratory variation for some serotypes. For serotypes 2, 8, and 11A, the variability was reduced by 40%, 45%, and 40%, respectively. For serotypes 12F, 17F, and 20B, the reductions were more modest (14%, 19%, and 24%, respectively). Standardization had little effect for the remaining serotypes. In many cases, the impact of normalization was blunted by the results from five sera that were collected after an extended post-vaccination interval.We have previously reported consensus values for 007sp for 13 serotypes, as well as the creation of a calibration serum panel (“Ewha Panel A”). Here, we report consensus values for 11 additional serotypes for 007sp and the creation of a second serum panel (“Ewha Panel B”). These consensus values will facilitate the development of next-generation PCVs.     

Incidence of myopericarditis after mRNA COVID-19 vaccination: A meta-analysis with focus on adolescents aged 12–17 years

BackgroundThe incidence of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12–17 years remains unknown. Therefore, we conducted a study to pool the incidence of myopericarditis following COVID-19 vaccination in this age group.MethodsWe did a meta-analysis by searching 4 electronic databases until February 6, 2023. The following main keywords were used: “COVID-19”, “vaccines”, “myocarditis”, “pericarditis”, and “myopericarditis”. Observational studies reporting on adolescents aged 12–17 years who had myopericarditis in temporal relation to receiving mRNA COVID-19 vaccines were included. The pooled incidence of myopericarditis and 95 % confidence interval (CI) were calculated using a single-group meta-analysis.ResultsFifteen studies were included. The pooled incidences of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12–17 years were 43.5 (95 % CI, 30.8–61.6) cases per million vaccine doses for both BNT162b2 and mRNA-1273 (39 628 242 doses; 14 studies), and 41.8 (29.4–59.4) cases for BNT162b2 alone (38 756 553 doses; 13 studies). Myopericarditis was more common among males (66.0 [40.5–107.7] cases) than females (10.1 [6.0–17.0] cases) and among those receiving the second dose (60.4 [37.6–96.9] cases) than those receiving the first dose (16.6 [8.7–31.9] cases). The incidences of myopericarditis did not differ significantly when grouped by age, type of myopericarditis, country, and World Health Organization region. None of the incidences of myopericarditis pooled in the current study were higher than those after smallpox vaccinations and non-COVID-19 vaccinations, and all of them were significantly lower than those in adolescents aged 12–17 years after COVID-19 infection.ConclusionsThe incidences of myopericarditis after mRNA COVID-19 vaccination among adolescents aged 12–17 years were very rare; they were not higher than other important reference incidences. These findings provide an important context for health policy makers and parents with vaccination hesitancy to weight the risks and benefits of mRNA COVID-19 vaccination among adolescents aged 12–17 years.     

Immunisation of migrants in EU/EEA countries: Policies and practices

In recent years various EU/EEA countries have experienced an influx of migrants from low and middle-income countries. In 2018, the “Vaccine European New Integrated Collaboration Effort (VENICE)” survey group conducted a survey among 30 EU/EEA countries to investigate immunisation policies and practices targeting irregular migrants, refugees and asylum seekers (later called “migrants” in this report). Twenty-nine countries participated in the survey. Twenty-eight countries reported having national policies targeting children/adolescent and adult migrants, however vaccinations offered to adult migrants are limited to specific conditions in seven countries. All the vaccinations included in the National Immunisation Programme (NIP) are offered to children/adolescents in 27/28 countries and to adults in 13/28 countries. In the 15 countries offering only certain vaccinations to adults, priority is given to diphtheria-tetanus, measles-mumps-rubella and polio vaccinations. Information about the vaccines given to child/adolescent migrants is recorded in 22 countries and to adult migrants in 19 countries with a large variation in recording methods found across countries. Individual and aggregated data are reportedly not shared with other centres/institutions in 13 and 15 countries, respectively. Twenty countries reported not collecting data on vaccination uptake among migrants; only three countries have these data at the national level. Procedures to guarantee migrants’ access to vaccinations at the community level are available in 13 countries. In conclusion, although diversified, strategies for migrant vaccination are in place in all countries except for one, and the strategies are generally in line with international recommendations. Efforts are needed to strengthen partnerships and implement initiatives across countries of origin, transit and destination to develop and better share documentation in order to guarantee a completion of vaccination series and to avoid unnecessary re-vaccination. Development of migrant-friendly strategies to facilitate migrants' access to vaccination and collection of vaccination uptake data among migrants is needed to meet existing gaps.     

Understanding medical students’ practices and perceptions towards vaccination in China: A qualitative study in a medical university

The qualitative study aims to understand and conceptualize Chinese medical students’ practices and perceptions towards vaccination. Focus groups (n = 5) were conducted through convenience sampling in a medical university in October 2016 in Anhui, China. Two years later, 6 participants among them were follow-up interviewed. All the interviews were audio-recorded, then transcribed verbatim, and analyzed using constant comparative method. Opinions of 22 participants (13 females, 9 males) were collected. Results revealed that hepatitis B vaccination was discussed the most frequently, and most of participants were vaccinated against (or had documented immunity to) hepatitis B before or during their clinical internship. None of the participants reported other vaccines uptake. Three dimensions of themes were identified: (i) at individual level, the factor “feeling less infection risk” might strengthen their perceived barriers. The factors “laziness” and “fluke mind” would be used to rationalize their inactive practices about vaccination; (ii) at social level, themes involved “inactive organizational behaviors”, “suggestions from people around”, and “social norms”. Decision-making of medical students’ vaccination was more relying on themselves and influenced more by their classmates before or during their internship, rather than being influenced more by their families/universities as before. (iii) at professional level, there are two contradictions about the participants’ behaviors and attitudes. One is that they may have inappropriate behaviors because of their lack of knowledge, but sometimes they seem too satisfied about their medical knowledge to vaccination. The other is that there are both vigilance response and desensitization to occupational infection risk. It is suggested that efforts should be strengthened to spread scientific knowledge of infectious diseases and immunization as long as medical students enter the university. Publicity and organizational activities should be strengthened, and related researches should be carried out by the government or scholars.     

A behavior change model to address caregiver hesitancy around COVID-19 vaccination in pediatrics

IntroductionMany families express hesitancy around immunizing their children against COVID-19. We sought to better understand the perspectives of vaccine hesitant caregivers, and develop targeted recommendations for health care workers and policymakers to engage in more effective vaccine discussions.MethodsWe conducted semi-structured telephone interviews with 23 caregivers recruited from a pediatric infectious diseases clinic, including a subset of patients referred to discuss vaccine hesitancy. Thematic analysis of the interviews identified themes that were mapped using behavior change models to identify perceived barriers and facilitators towards COVID-19 immunization.ResultsBarriers and facilitators were mapped to the WHO (World Health Organization) 3C’s (confidence, complacency, convenience) model of vaccine hesitancy as well as the COM-B (capability, opportunity, motivation) behavior change model. Barriers included mistrust in authorities, misperception of the risk of COVID-19 in children, and perceived health contraindications and negative previous vaccine experiences. Facilitators included positive relationships with healthcare workers, the promise of a “return to normal”, and societal pressures to immunize.ConclusionsEfforts to increase vaccine uptake in the pediatric population must target specific barriers and facilitators to immunization expressed by caregivers. To address these concerns, we suggest: 1. Educating hesitant caregivers by highlighting the long-term pandemic effects on children and the threat of COVID-19 to children’s health, 2. Building on the trust caregivers have in healthcare workers by involving frontline workers in public health policy, and 3. Harnessing the power of peer pressure by mobilization of societal pressures and establishing COVID-19 vaccination as the norm in children.     

Proteomic profiling of precipitated Clostridioides difficile toxin A and B antibodies

Clostridioides difficile infection is the leading cause of nosocomial diarrhoea globally. Immune responses to toxins produced by C. difficile are important in disease progression and outcome. Here, we analysed the anti-toxin A and anti-toxin B serum antibody proteomes following natural infection or vaccination with a C. difficile toxoid A/toxoid B vaccine using a modified miniaturised proteomic approach based on de novo mass spectrometric sequencing. Analysis of immunoglobulin variable region (IgV) subfamily expression in immunoprecipitated toxin A and toxin B antibodies from four and seven participants of a vaccine trial, respectively, revealed a polyclonal proteome with restricted IGHV, IGKV and IGLV subfamily usage. No dominant IGHV subfamily was observed in the toxin A response, however the dominant anti-toxin B heavy (H)-chain was encoded by IGHV3-23. Light (L)-chain usage was convergent for both anti-toxin A and anti-toxin B proteomes with IGKV3-11, 3-15, 3-20 and 4-1 shared among all subjects in both cohorts. Peptide mapping of common IgV families showed extensive public and private amino acid substitutions. The cohort responses to toxin A and toxin B showed limited similarity in shared IGHV subfamilies. L-chain subfamily usage was more similar in the anti-toxin A and anti-toxin B responses, however the mutational signatures for each subfamily were toxin-dependent. Samples taken both post vaccination (n = 5) or at baseline, indicating previous exposure (n = 2), showed similar anti-toxin B IgV subfamily usage and mutational profiles. In summary, this study provides the first sequence-based proteomic analysis of the antibody response to the major disease-mediating toxins of C. difficile, toxin A and toxin B, and demonstrates that despite the potential for extreme diversity, the immunoglobulin repertoire can raise convergent responses to specific pathogens whether through natural infection or following vaccination.     

Impact of aluminum adjuvants on the stability of pneumococcal polysaccharide-protein conjugate vaccines

Development of a vaccine drug product requires formulation optimization to ensure that the vaccine’s effectiveness is preserved upon storage throughout the shelf-life of the product. Although aluminum adjuvants have been widely used in vaccine formulations to safely and effectively potentiate an immune response, careful attention must be directed towards ensuring that the type of aluminum adjuvant does not impact the stability of the antigenic composition. PCV15 is a polysaccharide-protein conjugate vaccine comprising the pneumococcal polysaccharide (PnPs) serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F), each individually conjugated to the protein carrier CRM197. PCV15 was formulated with either amorphous aluminum hydroxyphosphate sulfate adjuvant (AAHS) or aluminum phosphate adjuvant (AP) and examined for both stability and immunogenicity. Using a collection of methods to evaluate vaccine stability, it was discovered that certain PCV15 serotypes (e.g., 6A, 19A, 19F) formulated with AAHS resulted in a reduction of immunogenicity in vivo and a reduction in recoverable dose as tested by an in vitro potency assay. The same polysaccharide-protein conjugates formulated with AP were stable regarding all measures tested. Moreover, the reduction in potency of certain serotypes correlated with chemical degradation of the polysaccharide antigen caused by the aluminum adjuvant as measured by reducing polyacrylamide gel electrophoresis (SDS-PAGE), High-Pressure Size Exclusion Chromatography coupled with UV detection (HPSEC-UV) and ELISA immunoassay. This study suggests a formulation, which includes AAHS, may negatively impact the stability of a pneumococcal polysaccharide-protein conjugate vaccine that contains phosphodiester groups. This decrease in stability would likely result in a decrease in the “active” concentration of antigen dose, and herein, it is shown that such instability directly compromised vaccine immunogenicity in an animal model. The results presented in this study help to explain critical degradation mechanisms of pneumococcal polysaccharide-protein conjugate vaccines.     

Safety surveillance of meningococcal group B vaccine (Bexsero®), Vaccine Adverse Event Reporting System, 2015–2018

BackgroundBexsero® (GlaxoSmithKline) is a four-component Neisseria meningitidis serogroup B vaccine (MenB-4C). It was licensed in the United States in 2015 for use among individuals ages 10–25 years. We aimed to assess the post-licensure safety profile of MenB-4C by examining reports received in the Vaccine Adverse Event Reporting System (VAERS).MethodsVAERS is a national passive surveillance system for adverse events (AEs) following immunization that uses the Medical Dictionary for Regulatory Activities to code reported AEs and the Code of Federal Regulations to classify reports by seriousness. In this case series, we analyzed U.S. reports involving MenB-4C received between January 23, 2015 through December 31, 2018. We used Empirical Bayesian data mining to identify MenB-4C/AE combinations reported at least twice as often as expected.ResultsVAERS received 1,867 reports following MenB-4C administration, representing 332 reports per million doses distributed. Most reports were for females (59%), with a median age of 17 years (interquartile range: 16–18 years); 40% of reports described simultaneous administration of other vaccines. The majority of reports were classified as non-serious (96%). The most commonly reported AEs were injection site pain (22%), pyrexia (16%), and headache (16%). Data mining identified disproportionate reporting for “injected limb mobility decreased” secondary to injection site reactions, including extensive swelling of the vaccinated limb and injection site pain.ConclusionsAnalysis of passive surveillance data from over 5.6 million doses of MenB-4C distributed in the United States did not reveal new safety concerns. The large majority of reports were classified as non-serious and the reported AEs were generally consistent with the safety experience described in clinical studies and the product’s package insert. While our results are reassuring, continued post-marketing surveillance is warranted.     

Subcutaneous nodules following immunization in children; in Victoria,Australia from 2007 to 2016

BackgroundSubcutaneous nodules are a rare adverse event following immunization (AEFI). We aimed to describe nodules at the injection site reported to SAEFVIC (Surveillance of Adverse Events Following Vaccination in the Community) using the Brighton Collaboration Case Definition (BCCD), management and recurrence following subsequent immunizations.MethodWe assessed 58 cases (<18 years of age) of ‘nodule at injection site’ reported to SAEFVIC, Melbourne, Australia, between May 2007 and June 2016. Case details were analyzed from records and phone interview follow-up. The Australian Immunization Registry was reviewed for immunization status.Results71% (41/58 reported cases) were consistent with the BCCD for subcutaneous nodule, 14% (8 cases) were ‘possible subcutaneous nodules’, 10% (6 cases) were nodules associated with BCG immunization and 5% (3 cases) were attributable to an alternative diagnosis. The median age at immunization was 12 months, (range 1 month–12 years); 54% male (22/41 cases). 17% (7 cases) had multiple nodules. Nodules were associated with immunizations containing aluminum (74%, 36/49 nodules), no aluminum (8%, 4 nodules) and unknown (18%, 9 nodules). Most cases developed symptoms within 3 days post-immunization (59%, 24 cases) and in the thigh (59%, 29 nodules). Pruritus was associated in 41% (17 cases). Around 1/3 (34%) of nodules resolved 6 months post immunization, 2/3 (68%) by 12 months, however 1/4 (24%) remained persistent for >24 months. 5 cases had prior nodules and 1 case had recurrence with subsequent immunization. 83% (34 cases) were fully immunized for age at follow-up.ConclusionSubcutaneous nodules at the injection site may occur following a wide range of vaccines, including vaccines without aluminum. All cases require careful review and where possible, specialist management and to support subsequent immunizations.     

Vaccine indicator and reminder band to improve demand for vaccination in Northern Nigeria: A qualitative evaluation of implementation outcomes

IntroductionVaccination coverage is low in Nigeria, partly due to poor demand for the vaccines. Till date, there is limited understanding of what works to improve demand for vaccination. A Vaccine Indicator and Reminder (VIR) band was designed to be worn on a child’s ankle to serve as a constant reminder to parents/caregivers on when to bring their children for vaccinations. This study assessed the acceptability of the band as a wearable reminder for infant vaccination in Kebbi State, Nigeria.MethodsA total of 503 infants who met the eligibility criteria were enrolled between August 2017 and February 2018. The intervention involved 1) sensitisation and mobilisation of community gatekeepers to advocate for immunisation; 2) engaging traditional birth attendants (TBAs) to refer mothers for vaccination and VIR bands; and 3) training facility-based health workers to secure the band on an eligible child. Focus group discussions and in-depth interviews were conducted at baseline (May 2016) and end-line (July 2018) with purposively selected participants. These interviews were analysed thematically.ResultsThere was general acceptability of the band at all levels, especially among community members who likened it to a “wristwatch” that constantly reminds mothers when next to vaccinate their children. The strong support from community leaders, TBAs and participating health workers increased acceptability of the band. Similarly, the VIR band’s aesthetics, ease of use and perceived benefits contributed to its acceptability. Wearing the VIR band was not perceived as an impediment because similar accessories are worn on new-borns. However, there were concerns about wearing accessories on the ankle, the red indicator colour, and the malfunctioning of some bands.ConclusionsThis study demonstrates that cultural adaptability of interventions and engagement with community structures are important in facilitating acceptability of new innovations. Further studies will evaluate the effectiveness of VIR band in improving vaccination coverage.     

Public opinion on global distribution of COVID-19 vaccines: Evidence from two nationally representative surveys in Germany and the United States

Despite ongoing calls for a more even global distribution of COVID-19 vaccines, there remains a great disparity between high- and low-income countries. We conducted representative surveys among the adult populations in the United States (N = 1,000) and Germany (N = 1,003) in June 2021 to assess public opinion in these countries on the distributive justice of COVID-19 vaccines. We conducted two instances of analytic hierarchy processes (AHP) to elicit how the public weighs different principles and criteria for vaccine allocation. In further discrete choice experiments, respondents were asked to split a limited supply of vaccine doses between a hypothetical high-income and a hypothetical low-income country. AHP weights in the United States and Germany were 37.4% (37.2–37.5) and 49.4% (49.2–49.5) for “medical urgency”, 32.7% (32.6–32.8) and 25.4% (25.2–25.5) for “equal access for all”, 13.7% (13.6–13.8) and 13.3% (13.2–13.4) for “production contribution”, and 16.3% (16.2–16.4) and 12.0% (11.9–12.1) for “free market rules”, respectively, with 95% CI shown in parentheses. In the discrete choice experiment, respondents in the United States and Germany split available vaccine doses such that the low-income country, which was three times more populous than the high-income country, on average received 53.9% (95% CI: 52.6–55.1) and 57.5% (95% CI: 56.3–58.7) of available doses, respectively. When faced with a dilemma where a vulnerable family member was waiting for a vaccine, 20.7% (95% CI: 18.2–23.3) of respondents in the United States and 18.2% (95% CI: 15.8–20.6) in Germany reduced the amount they allocated to the low-income country sufficiently to secure a vaccine for their family member. Our results indicate that the public in the United States and Germany favours utilitarian and egalitarian distribution principles of vaccines for COVID-19 over libertarian or meritocratic principles. This implies that political decisions favouring higher levels of redistribution would be supported by public opinion in these two countries.     

Development and immunogenicity evaluation of porcine deltacoronavirus inactivated vaccine with different adjuvants in mice

Porcine deltacoronavirus (PDCoV) is a novel coronavirus that causes diarrhea in pigs of various ages, especially in suckling piglets, and there are no effective measures to prevent and control PDCoV currently. In this study, two adjuvants Al(OH)₃ and ODN2395 working through different mechanisms were used to prepare inactivated PDCoV vaccines, and the immune effects of PDCoV inactivated vaccines were assessed in mice. From the results, we found that both PDCoV/Al(OH)₃ vaccine and PDCoV/2395 vaccine could induce IgG and neutralizing antibodies with high levels in mice. At the same time, cytokines of IFN-γ, IL-4 and chemokine ligand of CXCL13 in serum were significantly increased after immunization, and reached the highest levels in PDCoV/2395 vaccine group, which suggested that PDCoV/2395 could promote the production of both Th1 and Th2 polarized cytokines. In addition, histopathological observations showed that vaccination helped mice resist PDCoV infection. These results indicated that both the two inactivated vaccines have good immune effects. Moreover, the PDCoV/2395 vaccine worked better than the PDCoV/Al(OH)₃ vaccine for PDCoV/2395 having the good ability to induce both humoral and cellular immunogenicity. The PDCoV/2395 inactivated vaccine developed in this study might be an effective tool for the prevention of PDCoV infection.     

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

BackgroundOlder 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.MethodsThis 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.ResultsCoadministration 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.ConclusionsSafety 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.     

Dissociation of TRIF bias and adjuvanticity

Toll-like receptors (TLRs), a family of “pattern recognition receptors,” bind microbial and host-derived molecules, leading to intracellular signaling and proinflammatory gene expression. TLR4 is unique in that ligand-mediated activation requires the co-receptor myeloid differentiation 2 (MD2) to initiate two signaling cascades: the MyD88-dependent pathway is initiated at the cell membrane, and elicits rapid MAP kinase and NF-κB activation, while the TIR-domain containing adaptor inducing interferon-β (TRIF)-dependent pathway is initiated from TLR4-containing endosomes and results in IRF3 activation. Previous studies associated inflammation with the MyD88 pathway and adjuvanticity with the TRIF pathway. Gram-negative lipopolysaccharide (LPS) is a potent TLR4 agonist, and structurally related molecules signal through TLR4 to differing extents. Herein, we compared monophosphoryl lipid A (sMPL) and E6020, two synthetic, non-toxic LPS lipid A analogs used as vaccine adjuvants, for their capacities to activate TLR4-mediated innate immune responses and to enhance antibody production. In mouse macrophages, high dose sMPL activates MyD88-dependent signaling equivalently to E6020, while E6020 exhibits significantly more activation of the TRIF pathway (a “TRIF bias”) than sMPL. Eritoran, a TLR4/MD2 antagonist, competitively inhibited sMPL more strongly than E6020. Despite these differences, sMPL and E6020 adjuvants enhanced antibody responses to comparable extents, with balanced immunoglobulin (Ig) isotypes in two immunization models. These data indicate that a TRIF bias is not necessarily predictive of superior adjuvanticity.     

Oral vaccine of recombinant Lactococcus lactis expressing the VP1 protein of duck hepatitis A virus type 3 induces mucosal and systemic immune responses

Duck hepatitis A virus (DHAV) is the major pathogen of duck viral hepatitis, which has caused great economic losses to duck breeding industry. As an effective delivery tool for protein antigens, Lactococcus lactis (L. lactis) has been successfully used to stimulate mucosal and systemic immune response. In this study, a recombinant L. lactis named NZ3900-VP1 was constructed, which could express VP1 protein of DHAV type 3 (DHAV-3) by using a nisin-controlled expression (NICE) system. The animal experiment in both mice and ducklings were performed to detect the immune response and protection effect of oral vaccination by the recombinant L. lactis. The results showed that oral vaccination with L. lactis NZ3900-VP1 significantly induced specific anti-VP1 IgG antibodies and mucosal secretory immunoglobulin A (sIgA) of DHAV-3 in mice and ducklings, and cytokines including interleukin-2 (IL-2), interferon gamma (IFN-γ), interleukin-10 (IL-10) and interleukin-4 (IL-4). Notably, the ducklings vaccinated with L. lactis NZ3900-VP1 were effectively protected when facing natural infestation of DHAV-3, which indicated that the recombinant L. lactis could serve as an effective vaccine to prevent DHAV-3 infection in ducklings.