Protective Vaccine Research Articles

Cell binding tropism of rat hepatitis E virus is a pivotal determinant of its zoonotic transmission to humans

Classically, all hepatitis E virus (HEV) variants causing human infection belong to the genus Paslahepevirus (HEV-A). However, the increasing cases of rat HEV infection in humans since 2018 challenged this dogma, posing increasing health threats. Herein, we investigated the underlying mechanisms dictating the zoonotic potentials of different HEV species and their possible cross-protection relationships. We found that rat HEV virus-like particles (HEVVLPs) bound to human liver and intestinal cells/tissues with high efficiency. Moreover, rat HEVVLPs and infectious rat HEV particles penetrated the cell membrane and entered human target cells postbinding. In contrast, ferret HEVVLPs showed marginal cell binding and entry ability, bat HEVVLPs and avian HEVVLPs exhibited no binding and entry potency. Structure-based three-dimensional mapping identified that the surface spike domain of rat HEV is crucial for cell binding. Antigenic cartography indicated that rat HEV exhibited partial cross-reaction with HEV-A. Intriguingly, sera of HEV-A infected patients or human HEV vaccine Hecolin® immunized individuals provided partial cross-protection against the binding of rat HEVVLPs to human target cells. In summary, the interactions between the viral capsid and cellular receptor(s) regulate the distinct zoonotic potentials of different HEV species. The systematic characterization of antigenic cartography and serological cross-reactivity of different HEV species provide valuable insights for the development of species-specific diagnosis and protective vaccines against zoonotic HEV infection.

Outer membrane protein C is a protective and unique vaccine antigen against Shigella flexneri 3a

The anti-Shigella vaccine is one of the WHO’s top priorities. Every year the disease kills more than 200,000 people worldwide and poses a serious threat to children under 5 years of age and the elderly. Increasing antibiotic resistance and limitations in diagnostics emphasize the need to develop an effective vaccine. Recent research and clinical trials report multiple approaches used in Shigella-vaccine development. However, despite the efforts of researchers, pharmaceutical companies and health care organizations, there is no licensed vaccine against shigellosis available to the community. Here, we expressed, broadly characterized and demonstrated the protective properties of outer membrane protein C as an effective molecule serving as a universal antigen for Shigella vaccine. Most of the current approaches to the development of Shigella vaccine are based on the polysaccharide antigens, which are serotype specific and have always been challenging in terms of their high specificity, targeting the most exposed surface antigens identified for certain Shigella serotypes. Here, we confirm immunogenic and protective properties of the recombinant OmpC protein, which protects mice against a lethal dose of a virulent strain 2 weeks after active immunization.

Developing Correlates of Protection for Vaccines Is Needed More than Ever—Influenza, COVID-19 and RSV Infection

One of the greatest success stories of modern medicine is the prevention of infectious diseases by vaccination, most notably against smallpox and poliomyelitis. However, recent events, such as the 2009–2010 swine flu and the 2020 COVID-19 pandemics, as well as the continued emergence of highly pathogenic avian influenza viruses highlighted the fact that we still need to develop new vaccines, and perhaps we should be proactive, rather than reacting to epidemics and pandemics. However, the development of tools for evaluating novel vaccines has not been able to keep up with the rate of vaccine production. Humoral and cellular immune responses to vaccination have both been suggested to be important in preventing infections or ameliorating their consequences, although there is uncertainty regarding their exact roles and importance. This, together with the rapid development of new vaccines, means that the need for developing immunogenicity parameters, and even more importantly, reliable correlates of protection, is more important than ever.

Therapeutic effect of topical tamoxifen in murine cutaneous leishmaniasis caused by Leishmania major.

Iran is one of the endemic regions of cutaneous leishmaniasis (CL) caused by Leishmania major. There is no protective vaccine available against CL available, and the most effective strategy is a definitive treatment. Topical medications can be an excellent option for this purpose. Tamoxifen, a cancer control drug, has properties such as inducing cell apoptosis and anti-parasitic activity, which can be useful in controlling eukaryotic parasites such as Leishmania. The present study was conducted to investigate this theory in experimental CL caused by L. major. Forty female BALB/c mice aged 4 to 6 weeks were infected by injecting 1 × 106 L. major metacyclics (MRHO/IR/75/ER) in the base of the tail. After the appearance of Leishmania nodules, mice were divided into five test and control groups. Two drug formulations were used: tamoxifen 1% in ethanol and tamoxifen citrate ointment 0.1%. The effectiveness of each formula was evaluated by determining the mean size of the ulcers and parasite burden after a 28-day treatment period. Both formulations showed reduced ulcer mean sizes. However, only the tamoxifen citrate ointment group demonstrated a statistically significant reduction (P = 0.049). The parasite burden decreased by 40.83% for the ointment group and 33.67% for the ethanol solution. Other control groups showed lesser reductions. This study partially demonstrated the effectiveness of topical tamoxifen on CL lesions in a murine model. It can provide a basis for further research on the therapeutic effects of different topical tamoxifen formulations.

Recombinant avian-derived antiviral proteins cIFITM1, cIFITM3, and cViperin as effective adjuvants in inactivated H9N2 subtype avian influenza vaccines

Vaccine adjuvants, serving as non-specific immune enhancers, play a pivotal role in the immunoprevention and control of animal diseases. This study utilized prokaryotic expression systems to express and purify chicken-derived cIFITM1, cIFITM3, and cViperin, which were then formulated as adjuvants with H9N2 avian influenza virus antigens to create inactivated vaccines. These vaccines were administered to SPF chickens to investigate their immunopotentiating functions. Additionally, the proteins were assessed for their ability to act as standalone immune enhancers. The results demonstrated that cIFITM1, cIFITM3, and cViperin significantly elevated serum hemagglutination inhibition (HI) antibody titers. Notably, when used individually, these proteins markedly enhanced the antiviral capabilities of challenged chickens, leading to alleviated clinical symptoms, reduced tracheal virus replication, diminished virus shedding, and lessened histopathological damage, with cIFITM1 exhibiting the most pronounced effect. Furthermore, the protective efficacy of two H9N2 recombinant virus inactivated vaccines supplemented with cIFITM1 adjuvant was validated, achieving a 100 % vaccine protection efficiency. In conclusion, cIFITM1, cIFITM3, and cViperin as adjuvants for influenza vaccines effectively inhibit virus replication and shedding, highlighting their significant potential in influenza prevention and control.

Evaluating the effect of BCG vaccination for non-specific protection from infection in senior citizens during the COVID-19 pandemic: A randomised clinical trial

The Bacillus Calmette-Guérin (BCG) vaccine may induce non-specific protection against unrelated infections. We tested the effect of BCG on the risk of infections among Danish senior citizens. Single-blinded randomised controlled trial including 1676 volunteers >65 years. Participants were randomised 1:1 to BCG or placebo and followed for 12 months. The primary outcome was acute infection leading to medical contact. Secondary outcomes were verified SARS-CoV-2 infection, self-reported respiratory symptoms, and all-cause hospitalisation. Data was analysed using Cox regression models, estimating hazard ratios (HR) with 95% confidence intervals (CI). The incidence of acute infection was 52.1 and 58.2 per 100 person-years for BCG and placebo, respectively (HR=0.89, 95% CI=0.78-1.02). There was no effect of BCG on SARS-CoV-2 infections (0.97, 0.75-1.26) or all-cause hospitalisations (1.10, 0.80-1.50), but BCG was associated with more respiratory symptoms (1.21, 1.10-1.33). BCG reduced the incidence of acute infections among participants <75 years (0.82, 0.70-0.95) but not among those >75 years (1.14, 0.88-1.47). In participants, who were COVID-19 vaccinated before enrolment, BCG was associated with lower incidence of acute infections (0.65, 0.50-0.85). BCG did not reduce risk of acute infections among Danish seniors overall, but the effect was modified by age group and COVID-19 vaccination. ClinicalTrials.gov (NCT04542330) and EU Clinical Trials Register (EudraCT number 2020-003904-15). Full trial protocol is available at ClinicalTrials.gov. In a randomised clinical trial among Danish senior citizens, BCG vaccination did not reduce the overall risk of acute infection, but BCG was associated with reduced risk in participants <75 years and participants who received COVID-19 vaccines prior to enrolment.

Assessment of neutralizing antibody response as a correlate of protection against symptomatic SARS-CoV-2 infections after administration of two doses of the CoronaVac inactivated COVID-19 vaccine: A phase III randomized controlled trial

The emergence of variants of concerns of SARS-CoV-2 highlights the need for comprehensively elucidating the correlates of protection for different COVID-19 vaccine types. Inactivated COVID-19 vaccines are currently amongst the most widely administered vaccines globally. However, investigations into the correlates of protection for inactivated COVID-19 vaccines are relatively rare. Data from a phase III double-blind, randomized, placebo-controlled clinical trial (NCT0445659) that evaluated the efficacy and safety of the CoronaVac vaccine in healthcare professionals were utilized in this secondary analysis. Additionally, the correlation between neutralizing antibody levels measured by micro-cytopathic effect (CPE) neutralization assay and the occurrence of laboratory-confirmed infections was assessed using neutralizing antibodies measured in blood samples collected on day 28 after receiving two doses of the vaccine. Finally, the protective threshold required to provide 50% protection against symptomatic illness and virus infections was estimated. The risk of infection was negatively correlated with the levels of post-vaccination neutralizing antibodies measured on day 28 after the second dose. A neutralization titer of 30 (95% CI: 2-56) was predicted to provide 50% efficacy against symptomatic infection, whilst a titer of 42 (95% CI: 24-62) was predicted to provide 50% efficacy against total infection. Lastly, a neutralization titer of 247 (95% CI: 139-506) or higher was required to achieve 80% or higher protection against symptomatic infections. The results highlight the value of neutralizing antibody response as a correlate of protection, which can be used to inform future vaccine development and implementation. Further studies of immune correlates of protection for other vaccines are warranted.

A novel outer membrane vesicle adjuvant improves vaccine protection against Bordetella pertussis

Pertussis is a vaccine-preventable respiratory disease caused by the Gram negative coccobacillus Bordetella pertussis. The licensed acellular pertussis (aP) vaccines protect against disease but do not prevent bacterial colonization and transmission. Here, we developed and tested an intranasal vaccine composed of aP antigens combined with T-vant, a novel adjuvant derived from bacterial outer membrane vesicles, that elicits both mucosal and systemic immune responses. We hypothesized that immunization of mice with aP-T-vant would enhance mucosal immunity and eliminate B. pertussis in the respiratory tract. In contrast to mice immunized intramuscularly with the licensed aP vaccine, intranasal immunization with aP-T-vant eliminated bacteria in both the lung and nasopharynx. Protection was associated with IFN-gamma and IL-17-producing, non-circulating CD4 + T cells in the lung and nasopharynx, and sterilizing immunity in the nasopharynx was dependent on IL-17. Novel mucosal adjuvants, such as T-vant, warrant further investigation to enhance the efficacy of next generation pertussis vaccines.

The Saudi thoracic society guidelines for vaccinations in adult patients with chronic respiratory diseases

Abstract: Adult patients with chronic respiratory diseases (CRDs) are considered high risk group who are more likely to experience worse clinical outcomes if they acquire viral or bacterial infections. Vaccination is the best preventive tool to reduce the risk of infection and disease occurrence and to reduce the level of severity of complications associated with the various vaccine-preventable infections. These guidelines were developed by the Saudi Thoracic Society task force to emphasize the critical importance of improving the vaccine coverage rates in adult patients with CRD. They are intended to serve as a reference for healthcare practitioners managing CRD patients. The guidelines aimed to review the current knowledge related to vaccination efficacy in adult patients with CRD, based on the recent evidence and recommendations. Integrating the administration of the recommended vaccines in routine healthcare, such as during outpatient visits or before hospital discharge, is crucial for improving the vaccination rates in high-risk patients. The key strategies to address this public health priority include simplifying vaccination guidelines to enhance their accessibility and implementation by healthcare providers, increasing awareness in both the patients and healthcare providers that vaccines are not only intended for children. Additional strategies include maintaining continuous surveillance and advance research to discover novel vaccines. This approach aims to expand the range of preventable diseases and improve overall health and well-being. Vaccine hesitancy remains a significant challenge that necessitates a clear understanding of the community concerns. Providing appropriate education and communication, as well as addressing these concerns, are the crucial steps toward improving vaccine acceptance and uptake. By implementing these guidelines and multifaceted strategies, healthcare systems can optimize vaccine coverage and protection for patients with CRD, reduce the burden of vaccine-preventable complications, and improve the clinical outcomes in this vulnerable population.

Immunopeptidomics of Salmonella enterica Serovar Typhimurium-Infected Pig Macrophages Genotyped for Class II Molecules.

Salmonellosis is a zoonotic infection that has a major impact on human health; consuming contaminated pork products is the main source of such infection. Vaccination responses to classic vaccines have been unsatisfactory; that is why peptide subunit-based vaccines represent an excellent alternative. Immunopeptidomics was used in this study as a novel approach for identifying antigens coupled to major histocompatibility complex class II molecules. Three homozygous individuals having three different haplotypes (Lr-0.23, Lr-0.12, and Lr-0.21) were thus selected as donors; peripheral blood macrophages were then obtained and stimulated with Salmonella typhimurium (MOI 1:40). Although similarities were observed regarding peptide length distribution, elution patterns varied between individuals; in total, 1990 unique peptides were identified as follows: 372 for Pig 1 (Lr-0.23), 438 for Pig 2 (Lr.0.12) and 1180 for Pig 3 (Lr.0.21). Thirty-one S. typhimurium unique peptides were identified; most of the identified peptides belonged to outer membrane protein A and chaperonin GroEL. Notably, 87% of the identified bacterial peptides were predicted in silico to be elution ligands. These results encourage further in vivo studies to assess the immunogenicity of the identified peptides, as well as their usefulness as possible protective vaccine candidates.

Escherichia coli heat-labile enterotoxin B subunit as an adjuvant of mucosal immune combined with GCRV-II VP6 triggers innate immunity and enhances adaptive immune responses following oral vaccination of grass carp (Ctenopharyngodon idella)

The grass carp reovirus (GCRV) is the most major pathogen that has threatened the grass carp (Ctenopharyngodon idella) industry of China for years. Though the oral vaccine has many advantages, the current vaccines still do not provide complete protection. Therefor the exploration of new preventive strategies is urgently needed. In this study, heat-labile enterotoxin B subunit of Escherichia coli (LTB) was combined with VP6 from GCRV type II (GCRV-II) via Lactococcus lactis expression system to form a potent oral vaccine and determines if fusion of LTB to the protective vaccine antigen can enhance protection in the fish. The expression of recombinant protein was confirmed by Western-blotting and enzyme-linked immunosorbent assay. The rare minnow was set as the model for the evaluation of the experiment administrated orally. The immune response including the antibody titer and the immune-related gene expression, and the protective efficacy which included the virus loaded and the relative protection, were thoroughly investigated after the trial. The results indicated that LTB can significantly elicit a higher neutralizing antibody responses and enhanced T-cell priming, activities and proliferation in mononuclear cells from intestine, spleen and kidney tissues when compared to the VP6 vaccine alone. Moreover, the combined adjuvant can significantly up-regulate type I interferon signaling in different immune organs, especially the mucosa associated lymphoidtissue which could not be induced by VP6 along, result in the contribution of the improvement in adaptive immune responses of the fish. In addition, challenge study showed that LTB combined VP6 could greatly improve the relative percent survival of the fish during the virus infection. These results highlight that LTB has the potential value to be a mucosal adjuvant of the fish, approaching for improving the efficacy of vaccination against GCRV-II, which does elicit both non-specific and specific immune responses.

Discovery, recognized antigenic structures, and evolution of cross-serotype broadly neutralizing antibodies from porcine B-cell repertoires against foot-and-mouth disease virus.

It is a great challenge to isolate the broadly neutralizing antibodies (bnAbs) against foot-and-mouth disease virus (FMDV) due to its existence as seven distinct serotypes without cross-protection. Here, by vaccination of pig with FMDV serotype O and A whole virus antigens, we obtained 10 bnAbs against serotypes O, A and/or Asia1 by dissecting 216 common clonotypes of two serotype O and A specific porcine B-cell receptor (BCR) gene repertoires containing total 12720 B cell clones, indicating the induction of cross-serotype bnAbs after sequential vaccination with serotypes O and A antigens. The majority of porcine bnAbs (9/10) were derived from terminally differentiated B cells of different clonal lineages, which convergently targeted the conserved "RGDL" motif on structural protein VP1 of FMDV by mimicking receptor recognition to inhibit viral attachment to cells. Cryo-EM complex structures revealed that the other bnAb pOA-2 specifically targets a novel inter-pentamer antigen structure surrounding the viral three-fold axis, with a highly conserved determinant at residue 68 on VP2. This unique binding pattern enabled cross-serotype neutralization by destabilizing the viral particle. The evolutionary analysis of pOA-2 demonstrated its origin from an intermediate B-cell, emphasizing the crucial role of somatic hypermutations (SHMs) in balancing the breadth and potency of neutralization. However, excessive SHMs may deviate from the trajectory of broad neutralization. This study provides a strategy to uncover bnAbs against highly mutable pathogens and the cross-serotype antigenic structures to explore broadly protective FMDV vaccine.

An mRNA vaccine candidate encoding H5HA clade 2.3.4.4b protects mice from clade 2.3.2.1a virus infection

Highly pathogenic avian influenza (HPAI) H5 viruses from different clades have been circulating globally, threatening wild/domestic birds and mammals. Given frequent spillovers and high mortality among mammals, coupled with our inability to predict which clade of H5 virus has pandemic potential, cross-clade protective HPAI H5 vaccines are urgently needed. Here, we demonstrate the applicability of a lipid nanoparticle-based mRNA vaccine modality to induce cross-protective immunity against lethal HPAI virus infection.

Serotype independent protection induced by a vaccine based on the IgM protease of Streptococcus suis and proposal for a new immunity-based classification system

The IgM protease (IdeSsuis gene; Gene ID 8153996) of Streptococcus suis is a putative virulence factor that has been shown to be a protective vaccine antigen for pigs (Seele et al. Vaccine 33:2207–12, 2015). To assess its potential as a cross-protective antigen, the amino acid variability among prevalent clinical isolates in various regions and among various serotypes was investigated. Multi-sequence alignment of full-length amino acid sequences of S. suis IgM protease, available in the public domain (status Jan-2022) supplemented with in-house sequences, i.e. a total of 1999 sequences, revealed that the IgM protease of S. suis clusters into three main evolutionary distinct branches: groups A, B and C. Group A, 82% of the sequences in the database, was associated with clinical isolates of various serotypes. Group B, 6% of the strains in the database, was associated with clinical isolates mainly in the EU and mainly belonging to serotype (st) 9. Group C, 12% of the strains in the database, was largely associated with healthy carrier isolates, i.e. nose or tonsil isolates of various serotypes but in particular with st9 and un-typable strains. Within the groups A, B and C, high levels of amino acid identity were observed (> 75%), whereas between groups A and B, the percentage amino acid identity was approximately 30% and between groups A and C approximately 55%. Experimental Escherichia coli expressed recombinant subunit vaccines based on the IgM protease group A sequence of st1 strain B10-99, st2 strain 10 or st7 strain 14009-1, induced serotype independent protection in pigs against challenge with all group A strains tested, i.e. strains of different parts of the phylogenetic tree and of different serotypes including st1, 2, 9 and 14. Protection was observed after vaccination of piglets at 3 and 5 weeks of age and subsequent challenge at 7 weeks but also after vaccination of gilts at 6 and 2 weeks before anticipated parturition and challenge of the offspring up to at least 8 weeks of age. No protection was observed against challenge with st9 strain SZ2000-6264 having group B IgM protease. A recombinant subunit vaccine based on the group B IgM protease sequence, also did not protect against challenge with the homologous group B st9 challenge strain. The results indicate that a vaccine based on a group A IgM protease induces protection against all S. suis strains that express the group A IgM protease. Depending on the geographical region such a vaccine is expected to protect against 60–100% of the virulent S. suis strains. Since the novel proposed IgM protease classification is highly relevant, a PCR was developed and validated, to be able to classify clinical isolates into IgM protease groups A, B and C and predict the cross-protection that can be expected from a group A based IgM protease vaccine.

Aerosol immunization with influenza matrix, nucleoprotein, or both prevents lung disease in pig

Current influenza vaccines are strain-specific and require frequent updates to combat new strains, making a broadly protective influenza vaccine (BPIV) highly desirable. A promising strategy is to induce T-cell responses against internal proteins conserved across influenza strains. In this study, pH1N1 pre-exposed pigs were immunized by aerosol using viral vectored vaccines (ChAdOx2 and MVA) expressing matrix (M1) and nucleoprotein (NP). Following H3N2 challenge, all immunizations (M1, NP or NPM1) reduced lung pathology, but M1 alone offered the greatest protection. NP or NPM1 immunization induced both T-cell and antibody responses. M1 immunization generated no detectable antibodies but elicited M1-specific T-cell responses, suggesting T cell-mediated protection. Additionally, a single aerosol immunization with the ChAdOx vaccine encoding M1, NP and neuraminidase reduced lung pathology. These findings provide insights into BPIV development using a relevant large natural host, the pig.

5-year vaccine protection following a single dose of Vi-tetanus toxoid conjugate vaccine in Bangladeshi children (TyVOID): a cluster randomised trial

WHO currently recommends a single dose of typhoid conjugate vaccine (TCV) in high-burden countries based on 2-year vaccine efficacy data from large randomised controlled trials. Given the decay of immunogenicity, the protection beyond 2 years is unknown. We therefore extended the follow-up of the TyVAC trial in Bangladesh to assess waning of vaccine protection to 5 years after vaccination. We conducted a cluster randomised controlled trial (TyVAC; ISRCTN11643110) in Dhaka, Bangladesh, between 2018 and 2021. Children aged 9 months to 15 years were invited to receive a single dose of TCV or Japanese encephalitis vaccine between April 15, 2018, and November 16, 2019, based on the randomisation of their clusters of residence. Children who received the Japanese encephalitis vaccine were invited to receive TCV at the final visit between Jan 6, and Aug 31, 2021, according to the protocol. This follow-on study extended the follow-up of the original trial until Aug 14, 2023. The primary endpoint of this study was to compare the incidence of blood culture-confirmed typhoid between children who received TCV in 2018-19 (the previous-TCV group) and those who received the vaccine in 2021 (the recent-TCV group), to evaluate the relative decline in vaccine protection. We also did a nested study using the test-negative design comparing the recent-TCV and previous-TCV groups with unvaccinated individuals, as well as an immunogenicity study in a subset of 1500 children. Compared with the recent-TCV group, the previous-TCV group had an increased risk of typhoid fever between 2021-23, with an adjusted incidence rate ratio of 3·10 (95% CI 1·53 to 6·29; p<0·0001), indicating a decline in the protection of a single-dose of TCV 3-5 years after vaccination. The extrapolated vaccine effectiveness in years 3-5 was 50% (95% CI -13 to 78), and was validated using the test-negative design analysis, with a vaccine effectiveness of 84% (74 to 90) in the recent-TCV group and 55% (36 to 68) in the previous-TCV group, compared with unvaccinated individuals. Anti-Vi-IgG responses declined over the study period. The highest rate of decay was seen in children vaccinated at younger than 2 years in the original trial. The inverse correlation between age and the decay of antibodies was also seen in the subgroup analysis of vaccine effectiveness, where the youngest age group (<7 years at fever visits) exhibited the fastest waning, with vaccine effectiveness dropping to 24% (95% CI -29 to 55) at 3-5 years after vaccination. A decline in the protection conferred by a single-dose TCV was observed 3-5 years after vaccination, with the greatest decline in protection and immune responses observed in children vaccinated at younger ages. A booster dose of TCV around school entry age might be needed for children vaccinated while younger than 2 years to sustain protection against typhoid fever during the school years when the risk is the highest. The Bill & Melinda Gates Foundation.

Antibody responses to re-immunization in recipients of allogeneic hematopoietic cell transplantation

Abstract Background Immunologic memory against vaccine-preventable diseases is often lost after an allogeneic hematopoietic cell transplant (allo-HCT), therefore recipients are required to be re-immunized after allo-HCT to regain immunity against these infections. But the response to vaccination after an allo-HCT can be highly variable and is not well understood. We performed a single center retrospective study to examine immunization practices and determine the rate of vaccine protection and seroconversion following vaccination after allo-HCT. Methods Electronic medical records (EMR) from patients ≤18 years of age who underwent allo-HCT at St. Jude Childrens’ Research Hospital between 2005 - 2021 were reviewed. Clinical information and serology results before and after completion of the immunizations series were extracted from the EMR. The vaccines included in this analysis were diphtheria, measles, mumps, rubella (MMR), varicella, and polio. Protection was evaluated only for infections with established immune correlates. Seroconversion was defined as 4-fold increase in titers for vaccines with quantitative antibody assays, or as a change from negative to positive IgG for vaccines with qualitative antibody tests. Results 760 patients were included in this cohort. Demographic and clinical data are summarized in Table 1. The mean age at allo-HCT was 10.4 years, most were male (56.8%) and white (74.6%). Acute leukemia accounted for 66.4% of allo-HCT recipients. Conditioning was myeloablative for 53.45%, and reduced intensity for 37.9%. Most received transplants from mismatched-related donors, (44.9%), followed by matched unrelated donors (35.4%) and matched related donors (19.5%). The number of patients who received the full vaccination series at our institution differed by vaccine and ranged from 41-150, and the respective subsets with available pre-vaccination and post-vaccination titers ranged from 24-93. The median time from transplant to initiation of immunizations was 12 months (range: 6-58) for non-live vaccines, 25 months (range: 23, 63) for MMR vaccine, and 28 months (range: 16, 117)) for varicella vaccine. Protection post immunization varied, with less patients demonstrating protections for mumps (79%) and measles (82%) (Figure 1). Seroconversion also varied among the different vaccine components and types of vaccines. Conclusion Current strategies to re-immunize patients after allo-HCT do not provide protection to all patients. Understanding the factors associated with suboptimal immune responses is critical for advancing our knowledge in this area. Whether time-based approaches combined with immune reconstitution data are required to further optimize protection remains unclear. Additionally, different vaccine schedules (i.e., higher doses) may be required in these patients. Figure 1. Protection and seroconversion rate by vaccine target.

The 13-year long-term follow-up on the effectiveness and immunogenicity of the quadrivalent human papillomavirus vaccine in Chinese females vaccinated at 20–45 years of age

ABSTRACT The quadrivalent human papillomavirus (qHPV) vaccine demonstrated high efficacy against vaccine-type-related precancers in Chinese females through a 6.6-year double-blind, randomized control trial (V501–041, NCT00834106). We present results for its long-term follow-up (LTFU) phase, evaluating vaccine effectiveness and immunogenicity throughout 13 years post Dose 1. Participants receiving qHPV vaccines at ages 20–45 in the V501–041 study constituted the early vaccination group (EVG). Those who received the placebo in V501–041 but were vaccinated during 2018–2020 formed the catch-up vaccination group (CVG), while the control group (CG) comprised those remaining unvaccinated throughout V501–041 and LTFU. The primary endpoint was histopathologically-confirmed cervical intraepithelial neoplasia (CIN) 2+ tested PCR-positive for HPV-16/18. Antibodies against HPV-6, 11, 16, and 18 were assessed using an immunoglobulin G (IgG) Luminex immunoassay at year 13. A total of 1100 participants from V501–041, of whom 978 were followed in LTFU, were included with a median follow-up of 152.2 months. No cases of the primary endpoint were observed in the EVG during 5513.6 person-years of follow-up, while one case was observed in the CG over 2951.4 person-years of follow-up, indicating a 100% risk reduction in the EVG compared to the CG. In the CVG, no cases were detected from vaccination to the latest follow-up (0.0 per 10 000 person-years), contrasting with an incidence of 22.3 per 10 000 person-years prior to vaccination. Seropositivity rates at year 13 remained >92% (for HPV-6/11/16) and 84% (HPV-18). These findings demonstrated continued vaccine protection against cervical precancers and sustained immunogenicity through 13 years post-vaccination. Trial Registration The LTFU study was registered at the Chinese Clinical Trial Registry, ChiCTR2100052313.

Foot-and-mouth disease virus antigenic landscape and reduced immunogenicity elucidated in atomic detail

Unlike most other picornaviruses, foot-and-mouth disease (FMD) intact virions (146S) dissociate easily into small pentameric subunits (12S). This causes a dramatically decreased immunogenicity by a mechanism that remains elusive. Here, we present the high-resolution structures of 12S (3.2 Å) and its immune complex of a single-domain antibody (VHH) targeting the particle interior (3.2 Å), as well as two 146S-specific VHHs complexed to distinct sites on the 146S capsid surface (3.6 Å and 2.9 Å). The antigenic landscape of 146S is depicted using 13 known FMD virus-antibody complexes. Comparison of the immunogenicity of 146S and 12S in pigs, focusing on the resulting antigenic sites and incorporating structural analysis, reveals that dissociation of 146S leads to structural alteration and destruction of multiple epitopes, resulting in significant differences in antibody profiles/lineages induced by 12S and 146S. Furthermore, 146S generates higher synergistic neutralizing antibody titers compared to 12S, whereas both particles induce similar total FMD virus specific antibody titers. This study can guide the structure-based rational design of novel multivalent and broad-spectrum recombinant vaccines for protection against FMD.

Potent neutralization of SARS-CoV-2 variants by RBD nanoparticle and prefusion-stabilized spike immunogens

We previously described a two-component protein nanoparticle vaccine platform that displays 60 copies of the SARS-CoV-2 spike protein RBD (RBD-NP). The vaccine, when adjuvanted with AS03, was shown to elicit robust neutralizing antibody and CD4 T cell responses in Phase I/II clinical trials, met its primary co-endpoints in a Phase III trial, and has been licensed by multiple regulatory authorities under the brand name SKYCovioneTM. Here we characterize the biophysical properties, stability, antigenicity, and immunogenicity of RBD-NP immunogens incorporating mutations from the B.1.351 (β) and P.1 (γ) variants of concern (VOCs) that emerged in 2020. We also show that the RBD-NP platform can be adapted to the Omicron strains BA.5 and XBB.1.5. We compare β and γ variant and E484K point mutant nanoparticle immunogens to the nanoparticle displaying the Wu-1 RBD, as well as to soluble prefusion-stabilized (HexaPro) spike trimers harboring VOC-derived mutations. We find the properties of immunogens based on different SARS-CoV-2 variants can differ substantially, which could affect the viability of variant vaccine development. Introducing stabilizing mutations in the linoleic acid binding site of the RBD-NPs resulted in increased physical stability compared to versions lacking the stabilizing mutations without deleteriously affecting immunogenicity. The RBD-NP immunogens and HexaPro trimers, as well as combinations of VOC-based immunogens, elicited comparable levels of neutralizing antibodies against distinct VOCs. Our results demonstrate that RBD-NP-based vaccines can elicit neutralizing antibody responses against SARS-CoV-2 variants and can be rapidly designed and stabilized, demonstrating the potential of two-component RBD-NPs as a platform for the development of broadly protective coronavirus vaccines.