NPJ Vaccines最新文献

Lot release testing of diphtheria, tetanus and acellular pertussis vaccines traditionally relied on in vivo protection models involving challenge of laboratory animals with toxins. Meanwhile, many labs have switched to serological testing of these vaccines, which is often performed in separate in vivo assays, even if all components were formulated into one vaccine product. Here we describe the results of simultaneous serological potency determination of diphtheria (D), tetanus (T) and acellular pertussis (aP) antigens obtained following immunization of guinea pigs with multicomponent pediatric and booster vaccines from different manufacturers. The 4th World Health Organization (WHO) International Standard (IS) for diphtheria toxoid (No. 07/216) and the 4th WHO IS for tetanus toxoid (No. 08/218) were used as reference preparations. For aP, a pediatric vaccine batch containing the antigens pertussis toxoid, filamentous hemagglutinin, pertactin and fimbriae proteins type 2/3 was established as internal control. Quantification of IgG against D, T and aP antigens in guinea pig sera was performed using a hexaplex electrochemiluminescence immunoassay. We further provide proof-of-concept using experimental vaccine samples lacking or containing reduced amounts of diphtheria toxoid in the presence of full amounts of tetanus and pertussis antigens and alum adjuvant. Importantly, the assay confirmed dose-response relationships for all antigens tested and was able to detect diphtheria out-of-specification batches. The results confirmed the suitability of the protocol for combined serology batch release testing of DTaP combination vaccines as first measure towards implementation of full in vitro testing of DTaP vaccines. This report summarizes the data and the protocol used for validation prior to implementation of this method in routine batch release testing of DTaP vaccines, which led to replacement of in vivo challenge experiments in our laboratory following the 3 R (replace, reduce, refine) principle.

Tick-borne encephalitis virus (TBEV) vaccine breakthrough (VBT) infections are not uncommon in endemic areas. The clinical and immunological outcomes have been poorly investigated. We assessed the magnitude and specificity of virus-specific antibody and T cell responses after TBE in previously vaccinated subjects and compared the results with those of unvaccinated TBE patients and study subjects that received vaccination without VBT infection. Symptomatic TBEV infection of unvaccinated study subjects induced virus-specific antibody responses to the E protein and non-structural protein 1 (NS1) as well as T cell responses to structural and other non-structural (NS) proteins. After VBT infections, significantly impaired NS1-specific antibody responses were observed, while the virus-specific T cell responses to the NS proteins were relatively strong. VBT infection caused predominantly moderate to severe disease during hospitalization. The level of TBEV EDIII- and NS1-specific antibodies in unvaccinated convalescent patients inversely correlated with TBE severity and neurological symptoms early after infection.

A randomized, active-controlled, double-blind, first-in-human, phase 1 study was conducted in healthy Korean adults to evaluate the safety, tolerability, and immunogenicity of EuNmCV-5, a new pentavalent meningococcal vaccine targeting serogroups A, C, W, X, and Y. Sixty participants randomly received a single dose of either EuNmCV-5 or MenACWY-CRM, a quadrivalent vaccine containing serogroups A, C, W, and Y. Safety was assessed through monitoring anaphylactic reactions, adverse events for 28 days, and serious adverse events over 180 days. Immunogenicity was assessed via rabbit complement-dependent serum bactericidal antibody (rSBA) assay. EuNmCV-5 was safe, well-tolerated, and elicited a substantial antibody titer increase. The seroprotection rates exceeded 96.7%, and the seroconversion rates were over 85% for all the targeted serogroups. It showed higher seroconversion rates against serogroups A and C (p = 0.0016 and 0.0237, respectively) and elicited a substantial increase in GMT for all targeted serogroups compared to the MenACWY-CRM.ClinicalTrials.gov identifier: NCT05739292.

In 2022, the Australian Government listed the koala as endangered in several states due to habitat destruction, traffic strikes, dog attacks, and Chlamydia pecorum disease. This study evaluates a 10-year assessment of a Major Outer Membrane Protein-based vaccine's effectiveness against chlamydial disease in wild koalas from Southeast Queensland. Over a decade, 680 koalas were tracked, with five vaccine trials involving 165 koalas. While prior studies only offered up to two years of data, this study's extended period allowed a thorough evaluation of vaccine efficacy. Results showed that vaccinated koalas had significantly lower disease incidence, with a 64% reduction in chlamydial mortality. This vaccine demonstrated positive impacts on both male and female koalas, highlighting its crucial role in conserving the Australian koala population and mitigating the threats they face.

Avian influenza poses a severe threat to poultry production and global food security, prompting the development of vaccination programs in numerous countries. Modified live virus (MLV) vaccines, with their potential for mass application, offer a distinct advantage over existing options. However, concerns surrounding reversion, recombination, and unintended transmission have hindered the progress of MLV development for avian influenza in poultry. To address these concerns, we engineered reassortment-impaired, non-transmissible, safe, immunogenic, and protective MLVs through the rearrangement of internal gene segments and additional modifications to the surface gene segments HA and NA. The unique peptide marker aspartic acid-arginine-proline-alanine-valine-isoleucine-alanine-asparragine (DRPAVIAN) was incorporated into HA, while NA was modified to encode the chicken interleukin-18 (ckIL18) gene (MLV-H9N2-IL). In vitro, the MLV-H9N2 and MLV-H9N2-IL candidates demonstrated stability and virus titers comparable to the wild-type H9N2 strain. In chickens, the MLV-H9N2 and MLV-H9N2-IL candidates did not transmit via direct contact. Co-infection studies with wild-type virus confirmed that the altered HA and NA segments exhibited fitness disadvantages and did not reassort. Vaccinated chickens showed no clinical signs upon vaccination, all seroconverted, and the inclusion of ckIL18 in the MLV-H9N2-IL vaccine enhanced neutralizing antibody production. A significant decrease in viral loads post-challenge underscored the protective effect of the MLVs. The MLV-H9N2-IL vaccine, administered via drinking water, proved immunogenic in chickens in a dose-dependent manner, generating protective levels of neutralizing antibodies upon aggressive homologous virus challenge. In summary, this study lays the groundwork for safe MLVs against avian influenza suitable for mass vaccination efforts.

This study reports on the immunogenicity and biodistribution of H5 hemagglutinin (HA)-based self-amplifying (sa) mRNA vaccines in mice. Four sa-mRNA vaccines encoding either a secreted full-length HA, a secreted HA head domain, a secreted HA stalk domain, or a full-length membrane-anchored HA were investigated. All vaccines elicited an adaptive immune response. However, the full-length HA sa-RNA vaccines demonstrated superior performance compared to head and stalk domain vaccines. The antibody titers positively correlated with the vaccine dose. Cellular immune responses and antigen-specific IgA antibodies in the lungs were also observed. The comparison of the sa-mRNA vaccines encoding the secreted and membrane-anchored full-length HA revealed that anchoring of the HA to the membrane significantly enhanced the antibody and cellular responses. In addition to the injection site, the intramuscularly injected sa-mRNA-LNPs were also detected in the draining lymph nodes, spleen, and to a lesser extent, in the lung, kidney, liver, and heart.

Recent studies demonstrate that sociopolitical attitudes partially explain variance in (SARS-CoV-2) vaccine hesitancy and uptake. Other attitudes, such as those towards esoteric beliefs, complementary and alternative medicine (CAM), and religion, have also been proposed. However, pertinent studies provide limited direction for public health efforts, as the impact of such attitudes has been tested in isolation or on different outcomes. Moreover, related associations between SARS-CoV-2 immunization drivers as well as views towards other modes of immunization (e.g., routine pediatric immunization), remain unclear. Based on a sample of ~7400 survey participants (Germany), where esoteric belief systems and CAM (Waldorf, homeopathy) are rather prevalent, and controlling for other sociological factors, we found that (i) individuals with positive attitudes towards Waldorf education and homeopathy are significantly less likely to have received a (further) dose of SARS-CoV-2 vaccine compared to those with positive views of mainstream medicine; (ii) for the former, immunization decisions are primarily driven by external pressures, and for the latter overwhelmingly by voluntary considerations; (iii) attitudes influencing adult SARS-CoV-2 vaccine uptake similarly influence views towards routine pediatric immunization. Our findings provide significant evidence informing a more nuanced design of public health and communication campaigns, and pertinent policies.

Under the dual pressure of emerging zoonoses and the difficulty in eliminating conventional zoonoses, the strategic management of bird diseases through vaccination represents a highly efficacious approach to disrupting the transmission of zoonotic pathogens to humans. Immunization with a DNA vaccine yielded limited protection against avian pathogen infection. To improve its immunogenicity, the extracellular domain of duck-derived CD40L (designated as dusCD40L) was employed as a bio-adjuvant. Our findings unequivocally established the evolutionary conservation of dusCD40L across avian species. Notably, dusCD40L exhibited a compelling capacity to elicit robust immune responses from both B and T lymphocytes. Furthermore, when employed as an adjuvant, dusCD40L demonstrated a remarkable capacity to significantly augment the titers of neutralizing antibodies and the production of IFNγ elicited by a DNA vaccine encoding the prM-E region of an avian flavivirus, namely, the Tembusu virus (TMUV). Moreover, dusCD40L could strengthen virus clearance of the prM-E DNA vaccine in ducks post-TMUV challenge. This research study presents a highly effective adjuvant for advancing the development of DNA vaccines targeting TMUV in avian hosts. Additionally, it underscores the pivotal role of duCD40L as a potent adjuvant in the context of vaccines designed to combat zoonotic infections in avian species.

In 2022, a genotype IV (GIV) strain of Japanese encephalitis virus (JEV) caused an unprecedented and widespread outbreak of disease in pigs and humans in Australia. As no veterinary vaccines against JEV are approved in Australia and all current approved human and veterinary vaccines are derived from genotype (G) III JEV strains, we used the recently described insect-specific Binjari virus (BinJV) chimeric flavivirus vaccine technology to produce a JEV GIV vaccine candidate. Herein we describe the production of a chimeric virus displaying the structural prM and E proteins of a JEV GIV isolate obtained from a stillborn piglet (JEV_NSW/22) in the genomic backbone of BinJV (BinJ/JEV_NSW/22-prME). BinJ/JEV_NSW/22-prME was shown to be antigenically indistinguishable from the JEV_NSW/22 parental virus by K_D analysis and a panel of JEV-reactive monoclonal antibodies in ELISA. BinJ/JEV_NSW/22-prME replicated efficiently in C6/36 cells, reaching titres of >10⁷ infectious units/mL - an important attribute for vaccine manufacture. As expected, BinJ/JEV_NSW/22-prME failed to replicate in a variety of vertebrate cells lines. When used to immunise mice, the vaccine induced a potent virus neutralising response against JEV_NSW/22 and to GII and GIII JEV strains. The BinJ/JEV_NSW/22-prME vaccine provided complete protection against lethal challenge with JEV_NSW/22, whilst also providing partial protection against viraemia and disease for the related Murray Valley encephalitis virus. Our results demonstrate that BinJ/JEV_NSW/22-prME is a promising vaccine candidate against JEV.

Although Omicron RBD of SARS-CoV-2 accumulates many mutations, the backbone region (truncated RBD) of spike protein is highly conserved. Here, we designed several subunit vaccines by keeping the conserved spike backbone region of SARS-CoV-2 Omicron BA.1 subvariant (S-6P-no-RBD), or inserting the RBD of Delta variant (S-6P-Delta-RBD), Omicron (BA.5) variant (S-6P-BA5-RBD), or ancestral SARS-CoV-2 (S-6P-WT-RBD) to the above backbone construct, and evaluated their ability to induce immune responses and cross-protective efficacy against various SARS-CoV-2 variants and SARS-CoV. Among the four subunit vaccines, S-6P-Delta-RBD protein elicited broad and potent neutralizing antibodies against all SARS-CoV-2 variants tested, including Alpha, Beta, Gamma, and Delta variants, the BA.1, BA.2, BA.2.75, BA.4.6, and BA.5 Omicron subvariants, and the ancestral strain of SARS-CoV-2. This vaccine prevented infection and replication of SARS-CoV-2 Omicron, and completely protected immunized mice against lethal challenge with the SARS-CoV-2 Delta variant and SARS-CoV. Sera from S-6P-Delta-RBD-immunized mice protected naive mice against challenge with the Delta variant, with significantly reduced viral titers and without pathological effects. Protection correlated positively with the serum neutralizing antibody titer. Overall, the designed vaccine has potential for development as a universal COVID-19 vaccine and/or a pan-sarbecovirus subunit vaccine that will prevent current and future outbreaks caused by SARS-CoV-2 variants and SARS-related CoVs.