Live Vaccine Research Articles

Navigating Reproductive Care in Patients With Inflammatory Bowel Disease: A Comprehensive Review.

Inflammatory bowel disease [IBD] is often diagnosed in patients during their reproductive years. It is crucial that both healthcare providers and patients are adequately informed to avoid misguided decisions regarding family planning. One of the most important aspects during conception and pregnancy is to maintain disease remission, as disease activity is associated with adverse pregnancy outcomes. Apart from methotrexate, most conventional drugs used in IBD are considered low risk during conception and pregnancy. For newer agents, evidence is still limited. If needed, surgery must not be postponed and should ideally be performed in specialized centres. In most patients, delivery should be vaginal except for patients with complex perianal disease, with an ileoanal pouch anastomosis, or if there is an obstetric contraindication. In children exposed to biological treatments during pregnancy, the risk of infections appears to be low, and psychomotor development is probably not affected. Regarding immunizations, the standard vaccination schedule for inactivated vaccines should be followed for children exposed to biologics in utero. In the case of live vaccines, such as rotavirus, decisions should be individualized and take into consideration the risk-benefit ratio, particularly in developing countries. In this review, we provide a comprehensive and updated overview of aspects related to fertility, pregnancy, breastfeeding, and the impact on the care of children born to mothers with IBD. Both the available evidence and areas of uncertainty are discussed, with the goal of assisting healthcare professionals caring for IBD patients during this important stage of their lives.

Intranasal M2SR and BM2SR Vaccine Viruses Do Not Shed or Transmit in Ferrets

Background/Objectives: Live influenza vaccines are considered to stimulate better overall immune responses but are associated with safety concerns regarding shedding and the potential for transmission or reassortment with wild-type influenza viruses. Intranasal M2SR and BM2SR (M2- and BM2-deficient single replication), intranasal influenza viruses, have shown promise as broadly cross-reactive next-generation influenza vaccines. The replication deficiency, shedding, and transmissibility of M2SR/BM2SR viruses were evaluated in a ferret model. Methods: Wild-type influenza A and B control viruses replicated in upper respiratory organs and transmitted to both direct and aerosol contact ferrets, whereas M2SR and BM2SR influenza vaccine viruses were not detected in any tissues or in nasal washes after inoculation and were not recovered from any direct or aerosol contact ferrets. Mice were simultaneously infected with wild-type influenza A and M2SR viruses to assess reassortment potential. Sequence and PCR analyses of the genome recovered from individual virus plaques isolated from lung homogenates identified the origin of the segments as exclusively from the replicating wild-type virus. Results: These results indicate that M2SR and BM2SR influenza vaccine viruses are attenuated, do not shed or transmit, and have a low probability for reassortment after coinfection. Absence of shedding was further demonstrated in nasal swabs taken from subjects who were inoculated with H3N2 M2SR in a previously described Phase 1 clinical study. Conclusions: These results indicate that M2SR/BM2SR viruses have the potential to be used in a broader population range than current live influenza vaccines.

Virus-like Particles-Based Vaccine to Combat Neurodegenerative Diseases.

Neurodegenerative diseases are regarded as gradual, incurable conditions with an insidious onset. Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most prevalent neurodegenerative diseases reported globally. Developing effective treatment strategies for neurodegenerative diseases has remained a primary objective and a huge challenge for researchers. The therapeutic medications that are now approved for the treatment of neurodegenerative diseases merely treat the symptoms; the underlying pathology is not addressed. Therefore, the emergence of novel disease-modifying therapeutic modalities such as immunotherapy has opened a new path in developing effective treatments for neurogenerative diseases. Compared to other types of subunit active vaccines, virus-like particles (VLPs) are considerably more immunogenic as they present dense and repetitive viral antigen epitopes on their surface, which can trigger both humoral and cell-mediated immune responses. They are also a much safer option than the traditional inactivated and live-attenuated vaccines since they are devoid of viral genomes and are, therefore, non-pathogenic and non-infectious. Researchers have turned their attention to VLPs as an active immunotherapy candidate for AD due to the lessons learned from the AN1792 trial. Studies have shown that they effectively induce anti-Aβ, anti-tau, and anti-α-Synuclein antibodies while avoiding T-cell-related immune reactions in animal models of AD and PD. This review compiles the findings of preclinical animal model studies and clinical investigations on VLP-based vaccines for neurogenerative diseases thus far. The technical limitations and potential difficulties associated with the future application of VLP-based vaccines in patients with neurodegenerative diseases have also been covered.

CRISPR-Cas system positively regulates virulence of Salmonella enterica serovar Typhimurium

BackgroundSalmonella, a foodborne pathogen, possesses a type I-E clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated (Cas) system. We investigated the system’s role in regulating Salmonella virulence by deleting the CRISPR arrays and Cas operon.ResultsOur study demonstrates invasion and proliferation defects of CRISPR-Cas knockout strains in intestinal epithelial cells and macrophages owing to the repression of invasion and virulence genes. However, proliferation defects were not observed in the Gp91phox−/− macrophages, suggesting the system’s role in the pathogens’ antioxidant defense. We deduced that the CRISPR-Cas system positively regulates H2O2 importer (OmpW), catalase (katG), peroxidase (ahpC), and superoxide dismutase (soda and sodCI), thereby protecting the cells from oxidative radicals. The knockout strains were attenuated in in-vivo infection models (Caenorhabditis elegans and BALB/c mice) due to hypersensitivity against antimicrobial peptides, complement proteins, and oxidative stress. The attenuation in virulence was attributed to the suppression of LPS modifying (pmr) genes, antioxidant genes, master regulators, and effectors of the SPI-1 (invasion) and SPI-2 (proliferation) islands in knockout strains. The regulation could be attributed to the partial complementarity of the CRISPR spacers with these genes.ConclusionsOverall, our study extends our understanding of the role of the CRISPR-Cas system in Salmonella pathogenesis and its virulence determinants.

Molecular characterization and phylogenetic analysis of infectious laryngotracheitis virus isolates from commercial chicken flocks in Turkey.

Infectious laryngotracheitis virus (ILTV) causes an acute and highly contagious respiratory disease in poultry. Live-attenuated vaccines are generally used to control and prevent infectious laryngotracheitis (ILT). However, these vaccines can revert to a virulent form due to multiple passages and thereby become an ILT source. Hence, monitoring of ILTV in the field through molecular characterization is critically important for controlling infection and differentiating circulating isolates. In this study, we genotypically characterized and phylogenetically analyzed eight ILTV isolates from chicken flocks located in four different cities of Turkey between 2019 and 2022. For all isolates, we analyzed two regions of the infected cell protein 4 gene (ICP4-1 and ICP4-2) and the thymidine kinase (TK) gene. The isolates were 100%, 100%, and 99.8-100% identical to each other in the ICP4-1 and ICP4-2 gene fragments and the TK gene, respectively. None of the ICP4 sequences had a deletion at nt 272-283, confirming that they were field isolates. None of the isolates were predicted to have a T252M mutation in the thymidine kinase, suggesting that they have low virulence. The isolates were 100%, 99.36%, and 99.91% identical to Turkish ILTV isolates in their ICP4-1, ICP4-2, and TK gene region, respectively. Phylogenetic analysis based on the ICP4-1 and TK genes confirmed that the ILTV isolates are closely related to Turkish ILTV isolates. This suggests that these ILTVs were endemic isolates, which in turn suggests that the ILTV isolates circulating in Turkey were evolutionarily close, originated from the field, and had low virulence.

A multivalent RSV vaccine based on the modified vaccinia Ankara vector shows moderate protection against disease caused by RSV in older adults in a phase 3 clinical study

Respiratory syncytial virus (RSV) causes a significant disease burden in older adults. The live recombinant vaccine based on a nonreplicating modified vaccinia Ankara (MVA-BN) poxvirus, MVA-BN-RSV, encoding for multiple proteins of RSV subtypes A and B, was assessed for efficacy against respiratory disease caused by RSV.Adults aged ≥60 years, with or without underlying chronic conditions, were enrolled and randomized in a 1:1 ratio to receive a single dose of vaccine or placebo and were followed for disease caused by RSV infection during the 2022–2023 season. The 2 primary endpoints were RSV-associated lower respiratory tract disease (LRTD) with ≥3 and ≥ 2 symptoms; acute respiratory disease (ARD) was a key secondary endpoint. The humoral RSV-specific immune response was assessed at baseline and 14 days post-vaccination. Safety was evaluated by collection of solicited adverse events (AEs) and unsolicited AEs for 7 and 28 days post-vaccination respectively, and SAEs for the entire study period.In total, 18,348 participants were included in the final efficacy and safety analyses. Vaccine efficacy was 42.9 % (95 % CI: −16.1; 71.9) against RSV-associated LRTD with ≥3 symptoms, 59.0 % (95 % CI: 34.7; 74.3) against LRTD with ≥2 symptoms, and 48.8 % (95 % CI: 25.8; 64.7) against ARD. The primary objective was not met for LRTD with ≥3 symptoms since the lower bound of the 95 % CI was below 20 %, the prespecified success criterion. The vaccine-elicited immune response showed mean fold-increases of 1.7 for RSV A and B neutralizing antibodies and 2.9 and 4.3 for RSV-specific IgG and IgA, respectively. The vaccine displayed mild to moderate reactogenicity, and no safety concerns were identified.MVA-BN-RSV induced suboptimal protection against RSV-associated LRTD, likely due to suboptimal neutralizing antibody response. The vaccine had an acceptable safety profile and confirmed immunogenicity, overall showing promise for MVA-BN-vectored constructs targeting other diseases.Trial Registration:Clinicaltrials.gov Identifier NCT05238025 (Registered February 14, 2022).

A vaccine candidate based on baculovirus displaying chikungunya virus E1-E2 envelope confers protection against challenge in mice.

Chikungunya fever is a re-emerging mosquito-borne disease caused by the chikungunya virus (CHIKV) and produces acute arthritis that can progress to chronic disease with arthralgia. The first approved live-attenuated chikungunya vaccine has only recently become available for use in humans in the USA, but the access in endemic regions remains unmet. Here, we exploited the baculovirus display technology to develop a vectored vaccine candidate that exposes the CHIKV membrane proteins E1 and E2 on the baculovirus surface. Using recombinant baculovirus as vector vaccines has both productive and regulatory advantages: they are safe for handling and easy to produce in high titers and are non-pathogenic and non-replicative in mammals but have strong adjuvant properties by inducing humoral and cellular immune responses. CHIKV E1 and E2 envelope proteins with their own signal and transmembrane sequences were expressed on the surface of budded baculovirus virions. Immunization of C57BL/6 mice with non-adjuvanted recombinant baculovirus induced IgG antibodies against E2 with a predominant IgG2c subtype, neutralizing antibodies and a specific IFN-γ CD8+ T-cell response. Immunization with a second dose significantly boosted the antibody response, and mice immunized with two doses of the vaccine candidate were completely protected against challenge with CHIKV showing no detectable viremia or signs of disease. Altogether, baculovirus display of CHIKV envelope proteins served as an efficient vaccine platform against CHIKV.IMPORTANCEThe global spread of chikungunya virus (CHIKV) has disproportionately impacted the Americas that experienced a fourfold increase in 2023 in cases and deaths compared with the same period in 2022. The disease is characterized by acute fever and debilitating joint pain that can become chronic. Despite the socioeconomic burden related to the high morbidity rates of CHIKV infection, a vaccine for CHIKV is currently approved only in the USA. Vaccines are the most effective preventive measure against viral diseases, and advances in the development of different vaccine platforms such as nucleic acids and viral vectors have prompted the rapid deployment of vaccines to contain the COVID-19 pandemic. Here, we report the use of baculovirus display as a strategy for the design of a novel vaccine that provides sterilizing immunity in a mouse model of chikungunya disease. Our results encourage further research regarding the potential of baculovirus as platforms for human vaccine design.

Immune History Modifies Disease Severity to HPAI H5N1 Clade 2.3.4.4b Viral Challenge.

The most recent outbreak of highly pathogenic avian H5 influenza (HPAI) virus in cattle is now widespread across the U.S. with spillover events happening to other mammals, including humans. Several human cases have been reported with clinical signs ranging from conjunctivitis to respiratory illness. However, most of those infected report mild to moderate symptoms, while previously reported HPAI H5Nx infections in humans have had mortality rates upwards of 50%. We recently reported that mice with pre-existing immunity to A/Puerto Rico/08/1934 H1N1 virus were protected from lethal challenge from highly pathogenic clade 2.3.4.4b H5N1 influenza virus. Here, we demonstrate that mice infected with the 2009 pandemic H1N1 virus strain A/California/04/2009 (Cal09) or vaccinated with a live-attenuated influenza vaccine (LAIV) were moderately-to-highly protected against a lethal A/bovine/Ohio/B24OSU-439/2024 H5N1 virus challenge. We also observed that ferrets with mixed pre-existing immunity-either from LAIV vaccination and/or from Cal09 infection-showed protection against a HPAI H5N1 clade 2.3.4.4b virus isolated from a cat. Notably, this protection occurred independently of any detectable hemagglutination inhibition titers (HAIs) against the H5N1 virus. To explore factors that may contribute to protection, we conducted detailed T cell epitope mapping using previously published sequences from H1N1 strains. This analysis revealed a high conservation of amino acid sequences within the internal proteins of our bovine HPAI H5N1 virus strain. These data highlight the necessity to explore additional factors that contribute to protection against HPAI H5N1 viruses, such as memory T cell responses, in addition to HA-inhibition or neutralizing antibodies.

10 Optimizing implementation and continuous monitoring of a newborn screening program for severe combined immunodeficiency

Abstract Background Severe Combined Immunodeficiency (SCID) is an inborn error of immunity characterized by severely low T cell levels and function. Early diagnosis is essential to prevent serious infections and improve outcomes. Newborn screening (NBS) for SCID provides a way to detect SCID and other conditions associated with T cell lymphopenia in the neonatal period. Objectives 1) Optimize the implementation of a NBS program for SCID in British Columbia (BC), Canada; and 2) create a systematic method for monitoring the diagnoses and outcomes of infants with a positive screen to facilitate continuous improvement of the NBS program. Design/Methods An interdisciplinary working group comprised of immunologists, biochemical geneticists, and hematopathologists met at regular intervals prior to and after implementing NBS for SCID in BC. We developed an algorithm for the evaluation and initial management of infants with an abnormal NBS for SCID based on literature review and local expert consensus. Using a REDCap database, we tracked the prevalence, evaluation, diagnoses and outcomes of infants with a positive NBS. The database also monitored diagnoses and outcomes of children referred to Immunology outside of the NBS program. Plan-do-study-act cycles included creation of clinical and educational guidelines on SCID, optimization of abnormal NBS cut-off values, and reflex chromosomal microarray (CMA) testing of infants with confirmed T cell lymphopenia. Results Between October 3, 2022 and June 16, 2023, 28,816 initial samples were tested, and 30 infants had a positive screen for SCID. Of the 30 infants, 10 were ultimately diagnosed with conditions associated with T cell lymphopenia. Diagnosis led to avoidance of live viral vaccines and implementation of infection precaution measures. No infants experienced complications related to live viral vaccine administration, compared to 1 case in the preceding 12 months prior to NBS implementation. In February 2023, the threshold for an abnormal NBS was adjusted to achieve the goal positive screen frequency of 0.1%. Performing reflex CMA testing on infants with confirmed T cell lymphopenia led to rapid diagnosis of chromosomal microdeletion syndromes, avoiding unnecessary second tier testing. Since implementing NBS for SCID in BC, there have been no cases of SCID diagnosed outside of the NBS program. Conclusion Establishing an interdisciplinary working group and clinical database facilitated the smooth integration and continuous improvement of NBS for SCID in BC. This model can be applied to other healthcare systems to support teams and ensure the best possible outcomes for affected patients.

Molecular characterization of reassortant infectious bursal disease virus (IBDV) strains of genogroup A3B1 detected in some areas of Britain between 2020 and 2021

Infectious bursal disease virus (IBDV) causes a major immunosuppressive disease of chickens. As part of ongoing epidemiological surveillance for IBDV, the hypervariable region (HVR) of the VP2 capsid gene encoded by segment A, and a region of the VP1 polymerase gene, encoded by segment B, were sequenced from 20 IBDV-positive bursal samples obtained in 2020 and 2021, from 16 commercial British broiler farms. Birds had received a live IBDV vaccine at 17–22 days of age, and samples were obtained at 25–55 days of age. Of the 16 farms, none contained very virulent (vv) strains, one contained a classical virulent strain, two contained vaccine strains, and five contained sequences of reassortant strains with a vv segment A and a non-vv segment B belonging to genogroup A3B1. In eight of the farms, we identified the sequences of both genogroup A3B1 reassortant strains and vaccine strains in the same samples. Therefore, the majority of the farms (13/16 (81%)) contained genogroup A3B1 reassortant viruses. Of the flocks containing reassortant strains, 5/13 (38%) had HVR mutations Q219L, G254D, D279N, and N280T, consistent with a recently described Western European clade, but the rest had other mutations or no mutations, demonstrating that multiple clades were present in the samples. Taken together, vv strains were not detected, but reassortant strains predominated in the farms, which belonged to different clades, and were frequently found together with vaccine strains.

Long term T cell response and safety of a tetravalent dengue vaccine in healthy children

As robust cellular responses are important for protection against dengue, this phase 2 study evaluated the kinetics and phenotype of T cell responses induced by TAK-003, a live-attenuated tetravalent dengue vaccine, in 4–16-year-old living in dengue-endemic countries (NCT02948829). Two hundred participants received TAK-003 on Days 1 and 90. Interferon-gamma (IFN-γ) enzyme-linked immunospot assay [ELISPOT] and intracellular cytokine staining were used to analyze T cell response and functionality, using peptide pools representing non-structural (NS) proteins NS3 and NS5 matching DENV-1, -2, -3, and -4 and DENV-2 NS1. One month after the second TAK-003 dose (Day 120), IFN-γ ELISPOT T cell response rates against any peptide pool were 97.1% (95% CI: 93.4% to 99.1%), and similar for baseline dengue seropositive (96.0%) and seronegative (98.6%) participants. IFN-γ ELISPOT T cell response rates at Day 120 were 79.8%, 90.2%, 77.3%, and 74.0%, against DENV-1, -2, -3, and -4, respectively, and remained elevated through 3 years post-vaccination. Multifunctional CD4 and CD8 T cell responses against DENV-2 NS peptides were observed, independent of baseline serostatus: CD8 T cells typically secreted IFN-γ and TNF-α whereas CD4 T cells secreted ≥ 2 of IFN-γ, IL-2 and TNF-α cytokines. NAb titers and seropositivity rates remained substantially elevated through 3 years post-vaccination. Overall, TAK-003 was well tolerated and elicited durable T cell responses against all four DENV serotypes irrespective of baseline serostatus in children and adolescents aged 4–16 years living in dengue-endemic countries. TAK-003-elicited CD4 and CD8 T cells were multifunctional and persisted up to 3 years post-vaccination.

Evaluation of the Protective Efficacy of Different Doses of a Chlamydia abortus Subcellular Vaccine in a Pregnant Sheep Challenge Model for Ovine Enzootic Abortion.

Chlamydia abortus causes the disease ovine enzootic abortion, which is one of the most infectious causes of foetal death in small ruminants worldwide. While the disease can be controlled using live and inactivated commercial vaccines, there is scope for improvements in safety for both sheep and human handlers of the vaccines. We have previously reported the development of a new prototype vaccine based on a detergent-extracted outer membrane protein preparation of C. abortus that was determined to be more efficacious and safer than the commercial vaccines when administered in two inoculations three weeks apart. In this new study, we have developed this vaccine further by comparing its efficacy when delivered in one or two (1 × 20 µg and 2 × 10 µg) doses, as well as also comparing the effect of reducing the antigen content of the vaccine by 50% (2 × 5 µg and 1 × 10 µg). All vaccine formulations performed well in comparison to the unvaccinated challenge control group, with no significant differences observed between vaccine groups, demonstrating that the vaccine can be administered as a single inoculation and at a lower dose without compromising efficacy. Future studies should focus on further defining the optimal antigen dose to increase the commercial viability of the vaccine.

In silico investigation of therapeutic potential of phytosteroids against SARS-CoV2 infection via inhibition of viral multiplication and attenuation of host cytokine storm

SARS-CoV2 infection overcomes host cell membrane barrier, followed by utilization of host cellular processes for viral multiplication. Simultaneously, it triggers a cytokine storm within and around infected cells and tissues. Anti-inflammatory agents that can potentially inhibit viral penetration and multiplication within the host cells may be ideal drug candidates against COVID-19. Dietary phytosteroids have significant anti-inflammatory potential. Hence, the present study intends to investigate anti-viral potential of three dietary phytosteroids, namely, brassinolide, 28-homocastasterone and 24-epibrassinolide against SARS-CoV2 proteins, S1 spike protein, nucleocapsid protein and main protease enzyme, in addition to host pro-inflammatory proteins, interleukin-1, tumour necrosis factor-α, cyclooxygenase-2 and prostaglandin synthase, as drug targets. Molecular docking studies by AutoDock version 4.0 was performed. Brassinolide, 28-homocastasterone and 24-epibrassinolide exhibits high docking score against all the seven proteins, as compared to hydroxychloroquine. Brassinolide and 28- homocastasterone has maximum binding affinity for pro-inflammatory proteins and SARS-CoV2 proteins.Dietary phytosteroids may potentially attenuate cytokine storm with simultaneous inhibition of host entry and multiplication of SARS-CoV2. In-vitro and in-vivo anti-viral studies of plant steroids may provide a clear path for the identification and development of novel drug candidates against COVID-19, that also provides evidence for the concept of reverse pharmacognosy.

Pooled safety evaluation for a new single-shot live-attenuated chikungunya vaccine.

Chikungunya disease, caused by chikungunya virus (CHIKV), is associated with substantial morbidity, including debilitating CHIKV-related arthralgia. Three clinical trials of a CHIKV vaccine (VLA1553, IXCHIQ®) were conducted in the US: a Phase 1 dose-finding trial, a pivotal Phase 3 trial, and a Phase 3 lot-to-lot consistency trial. Participants were healthy adults (≥18 years) and received a single intramuscular dose of VLA1553 (3520 participants) or placebo (1033 participants). Solicited injection site and systemic adverse events (AEs) (10 to 14 days post-vaccination), unsolicited AEs (28 and 180 days post-vaccination), AEs of special interest (AESIs) (28 days post-vaccination), medically attended AEs (MAAEs), serious AEs (SAEs) (180 days post-vaccination), and pregnancies were evaluated. Safety data were pooled, and analyses were descriptive. Overall, 63.7% of participants receiving VLA1553 experienced AEs, (44.7% for placebo), that were generally mild. Solicited injection site AEs, solicited systemic AEs, and unsolicited (Day 29) AEs were reported by 15.5%, 50.9%, 22.7% of participants who received VLA1553 and 11.1%, 26.9%, 13.4% who received placebo. Arthralgia was reported by 16.7% of participants who received VLA1553 and 4.8% of participants who received placebo; none required medical attention. MAAEs, AESIs, and SAEs were reported by 12.4%, 0.3%, 1.5% of participants who received VLA1553 and 11.3%, 0.1%, 0.8% of participants who received placebo. Protocol-defined AESIs were mild and short-lived, and two VLA1553-related SAEs resolved without sequelae. There were no clinically important differences in AE incidence based on age or medical history, and no VLA1553-related adverse pregnancy outcomes. There were 3 deaths (2 in the VLA1553 group and 1 in the placebo group), none was vaccine-related. A single dose of VLA1553 presented with an excellent local tolerability profile and overall safety in line with that expected for a live-attenuated vaccine. The safety profile was comparable in participants aged 18-64 years and ≥65 years.

Partial Sequence Analysis of Commercial Peste des Petits Ruminants Vaccines Produced in Africa

Peste des petits ruminants virus (PPRV), which is the only member of the Morbillivirus caprinae species and belongs to the genus Morbillivirus within the Paramyxoviridae family, causes the highly contagious viral sickness “Peste des petits ruminants (PPR).” PPR is of serious economic significance for small ruminant production, particularly in Africa. Control of this critical disease depends highly on successful vaccination against the PPRV. An in-depth understanding of the genetic evolution of the live-attenuated PPR vaccine Nigeria 75/1 strain used in Africa is essential for the successful eradication of this disease by 2030. Therefore, this study investigated the possible genetic evolution of the PPR vaccine produced by various African laboratories compared with the master seed available at AU-PANVAC. RT-PCR was performed to amplify a segment of the hypervariable C-terminal part of the nucleoprotein (N) from commercial batches of PPR vaccine Nigeria 75/1 strain. The sequences were analyzed, and 100% nucleotide sequence identity was observed between the master seed and vaccines produced. The results of this study indicate the genetic stability of the PPR vaccine from the Nigeria 75/1 strain over decades and that the vaccine production process used by different manufacturers did not contribute to the emergence of mutations in the vaccine strain.

Untangling lineage introductions, persistence and transmission drivers of HP-PRRSV sublineage 8.7

Despite a rapid expansion of Porcine reproductive and respiratory syndrome virus (PRRSV) sublineage 8.7 over recent years, very little is known about the patterns of virus evolution, dispersal, and the factors influencing this dispersal. Relying on a national PRRSV surveillance project established over 20 years ago, we expand the available genomic data of sublineage 8.7 from China. We perform independent interlineage and intralineage recombination analyses for the entire study period, which showed a heterogeneous recombination pattern. A series of Bayesian phylogeographic analyses uncover the role of Guangdong as an important infection hub within Asia. The spatial spread of PRRSV is highly linked with a composite of human activities and the heterogeneous provincial distribution of the swine industry, largely propelled by the smaller-scale Chinese rural farming systems in the past years. We sequence all four available modified live vaccines (MLVs) and perform genomic analyses with publicly available data, of which our results suggest a key “leaky” period spanning 2011–2017 with two concurrent amino acid mutations in ORF1a 957 and ORF2 250. Overall, our study provides an in-depth overview of the evolution, transmission dynamics, and potential leaky status of HP-PRRS MLVs, providing critical insights into new MLV development.

Facilitators and barriers to revaccination after hematopoietic stem cell transplantation among pediatric patients in Ecuador

Abstract Background Revaccination after hematopoietic stem cell transplantation (HSCT) is a challenge in areas where there is variability of access to vaccines and where special schedules are unfamiliar to physicians and primary care providers. We report the experience of re-immunization practices in pediatric patients after HSCT in Ecuador. Methods The database and medical charts of pediatric patients who had been in follow after HSCT from 2021 to 2023 in Solca Guayaquil was reviewed in order to assess the completeness of the revaccination schedule and to identify facilitators and barriers in implementation of the process. Patients with pediatric infectious diseases follow up where included. Results There were 30 patients who underwent HSCT during the reviewed period. Among them, 7 were excluded because they had not been seen by pediatric infectious diseases. Four patients who had their HSCT before the studied period were later added as they received follow-up by the specialty, therefore a total of 27 patients were included. There were 16 (59.3%) boys, mean age was 11 years (SD 3.6), and 16 (59.3%) lived outside Guayaquil. The most common diseases prompting HSCT were 14 (51.9%) lymphoblastic leukemia, 4 (14.8%) myeloid leukemia, 3 (11.1%) for Hodgkin lymphoma and 3 (11.1%) aplastic anemia. HSCT was performed outside Ecuador in 15 (55.6%) cases. Reimmunization schedule had been initiated in 21 (77.7%) of patients. Public health system was used exclusively in 11 (52.4%) cases, a combination of private and public system in 8 (38.1%) cases and exclusively private system in 2 (9.5%) cases. Among them, 9 (42.9%) had completed all recommended inactivated vaccines. Mean number of visits required for this was 5.1 (SD 1.9). After completion of inactivated vaccines, live vaccines where recommended and had been completed by 2 (9.5%) patients. The main facilitator identified was vaccine confidence and adherence to physician recommendations while the main barriers identified where health system related: a) Lack of awareness in public vaccination centers about special schedules, b) lack of availability of age licensed vaccines in public system and c) Lack of documentation of immunization administrated. Conclusion Health system related logistics (vaccine availability, knowledge of special schedules, coordination with immunization centers) continues to be a main barrier to complete recommended reimmunization schedule after HSCT while confidence in vaccines and adherence is the main facilitator in Ecuador. Government interventions need to be implemented in order to facilitate the process for this population of patients. Figure 1. Revaccination after hematopoietic stem cell transplantation in Solca Guayaquil (2021 – 2023).

Viral epitope profiling of hematopoietic cell transplant recipients with respiratory syncytial virus upper respiratory tract and lower respiratory tract infections

Abstract Background The pre-fusion conformation of the F glycoprotein of respiratory syncytial virus (RSVpreF) has been the target of recent respiratory syncytial virus (RSV) therapies, including monoclonal antibodies for immunocompetent children and vaccines for the elderly. However, the utility of targeted therapies against RSVpreF is unknown in pediatric or adult hematopoietic cell transplant (HCT) recipients, and there are limited natural history studies characterizing humoral immune responses after RSV infection in HCT recipients. We utilized VirScan, a novel high-throughput profiling of antiviral antibody epitopes, to identify differences in global RSV-related epitope hits after an RSV infection. Methods We evaluated adult and pediatric allogeneic HCT recipients who acquired RSV from 12/2011 to 12/2019. Patients were categorized into 3 groups: upper respiratory tract infections (URTI) only, those who progressed from URTI to lower respiratory tract infections (progressors) and lower respiratory tract infections (LRTI) at diagnosis, and tested at baseline prior to infection (pre-RSV), at RSV URTI or LRTI diagnosis (RSV diagnosis), at LRTI progression (LRTI), 4-6 weeks after infection (Response 1) and >8 weeks after infection (Response 2), depending on sample availability. We interrogated the viral antibody repertoire using a serosurvey (VirScan) that detects immunoglobulin G responses to 206 viruses. VirScan metrics evaluated included: (1) number of RSV epitope hits, (2) log10 of the maximum RSV epitope binding signal (EBS), analogous to an antibody titer for each epitope, and (3) geometric mean of all RSV EBS. Kruskal-Wallis tests were used to compare groups for each VirScan metric at the different time points. Results A total of 129 samples from 39 patients were analyzed; 24 with URTI only, 8 progressors, and 7 with LRTI at diagnosis. At each time point, VirScan metrics were similar among the 3 patient groups (Table 1). Though patterns of VirScan metrics following RSV diagnosis varied by patient, most showed a modest increase in values (Figure 1). Conclusion In this preliminary study, we utilized the power of VirScan, a comprehensive serologic profiling tool of the entire human virome, to characterize RSV specific antibody changes after RSV infection in allogeneic HCT recipients. There were no differences in global RSV VirScan metrics between the 3 groups, suggesting that antibodies may not be the primary driver of viral infection attenuation in this population. Future analyses will focus on differences in individual epitope acquisition, including RSVpreF, between the 3 groups, and investigate possible interactions with humoral responses to other viruses. Figure 1. Longitudinal RSV VirScan metrics for each patient separated by 3 groups (top row: RSV URTI only; middle row: progressors from URTI to LRTI; bottom row: LRTI at diagnosis). Each line is an individual patient. The different panels show the changes in RSV related epitope hits (A), the log10 maximum epitope binding signal (EBS) among RSV epitopes (B), and the geometric mean of all the RSV related EBS (C). Open circles represent time points prior to RSV diagnosis, filled circles represent time points just prior to, on or after URTI, and asterisks represent time points just prior to, on, or after LRTI.

Assessment of PPMV-1 Genotype VI Virulence in Pigeons and Chickens and Protective Effectiveness of Paramyxovirus Vaccines in Pigeons.

Pigeon paramyxovirus serotype 1 (PPMV-1), an antigenic and host variant of avian paramyxovirus Newcastle disease virus (NDV), primarily originating from racing pigeons, has become a global panzootic. Egypt uses both inactivated PPMV-1 and conventional NDV vaccines to protect pigeons from disease and mortality. However, the impact of prevalent strains and the effectiveness of available vaccines in pigeons in Egypt are unclear. This study investigates the virulence of PPMV-1 (Pigeon/Egypt/Sharkia-19/2015/KX580988) and evaluates available paramyxovirus vaccines in protecting pigeons against a PPMV-1 challenge. Ten-day-old specific-pathogen-free (SPF) embryonated chicken eggs infected with this strain exhibited a mean death time (MDT) of 86.4 ± 5.88 h. The intracerebral pathogenicity index (ICPI) in day-old chickens was 0.8, while pigeons experienced an ICPI of 0.96 and an intravenous pathogenicity index (IVPI) of 2.11. These findings classify the strain as virulent and velogenic. Experimental infection of pigeons with this PPMV-1 strain at 106 EID50/0.1 mL resulted in a 62.5% mortality rate, displaying nervous and enteric distress. The virus caused extensive lesions in visceral organs, with strong immunohistochemistry signals in all examined organs, indicating the systemic spread of the virus concurrent to its neurotropic and viscerotropic tropism. Furthermore, vaccination using an inactivated PPMV-1 and live NDV LaSota vaccine regimen protected 100% of pigeons against mortality, while with a single NDV LaSota vaccine, it was 62.5%. The PPMV alone or combined with NDV LaSota induced protective levels of haemagglutination inhibition (HI) antibody titres and reduced virus shedding from buccal and cloacal cavities. Based on generalised linear gamma model analysis, both PPMV-1 and NDV LaSota are antigenically comparable by HI. These findings suggest that using both inactivated PPMV-1 (G-VI) and live attenuated NDV (LaSota) vaccines is an effective prophylactic regimen for preventing and controlling PPMV-1 and NDV in pigeons, thereby reducing the risk of interspecies transmission.

Attenuated African swine fever viruses and the live vaccine candidates: a comprehensive review.

The African swine fever virus (ASFV) is spreading worldwide and causing huge economic losses to the global pig industry. The ASFV genome is 170-193 kb in length, contains approximately 150 open reading frames, and encodes more than 200 proteins, most of which have unknown functions. Owing to the unique viral structure, replication strategy, large number of genes of unknown function, and complicated pathogenesis, vaccine development research is challenging. Several naturally attenuated ASFV isolates have been extensively investigated and many genetically manipulated, gene-deleted, and cell-adapted ASFVs have been reported. Currently, live attenuated viruses prepared from weakly virulent strains are an efficient method to provide effective protection in vaccinated pigs; however, these have seldom been widely approved for vaccine use, except in Vietnam. Herein, we summarize the attenuated isolates or vaccine candidates for live vaccines derived from different sources, including naturally mutated, attenuated, cell-adapted, and genetically modified recombinant ASFVs. This will help to understand the gene function and immunogenicity of attenuated live ASFV, as well as the shortcomings of these viruses as vaccine candidates, and provide clues to prepare live, efficient, and safe vaccines for African swine fever.IMPORTANCEOutbreaks of African swine fever (ASF) have caused devastating losses to the global pig industry. Pigs immunized with ASFV attenuated virus can resist the lethal challenge of a strongly virulent virus. Here, we summarize the virulence of naturally mutated, cell-adapted, and genetically recombinant ASFV for pigs, and the protective effect after facing an attack challenge. We also analyze the advantages and disadvantages of ASFV attenuated viruses as vaccine candidates to provide clues for the preparation of efficient and safe live African swine fever vaccines.