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Microbiology Spectrum Feb 2023The production of enterovirus virus-like particles (VLPs) that lack the viral genome have great potential as vaccines for a number of diseases, such as poliomyelitis and...
The production of enterovirus virus-like particles (VLPs) that lack the viral genome have great potential as vaccines for a number of diseases, such as poliomyelitis and hand, foot, and mouth disease. These VLPs can mimic empty capsids, which are antigenically indistinguishable from mature virions, produced naturally during viral infection. Both in infection and , capsids and VLPs are generated by the cleavage of the P1 precursor protein by a viral protease. Here, using a stabilized poliovirus 1 (PV-1) P1 sequence as an exemplar, we show the production of PV-1 VLPs in Pichia pastoris in the absence of the potentially cytotoxic protease, 3CD, instead using the porcine teschovirus 2A (P2A) peptide sequence to terminate translation between individual capsid proteins. We compare this to protease-dependent production of PV-1 VLPs. Analysis of all permutations of the order of the capsid protein sequences revealed that only VP3 could be tagged with P2A and maintain native antigenicity. Transmission electron microscopy of these VLPs reveals the classic picornaviral icosahedral structure. Furthermore, these particles were thermostable above 37°C, demonstrating their potential as next generation vaccine candidates for PV. Finally, we believe the demonstration that native antigenic VLPs can be produced using protease-independent methods opens the possibility for future enteroviral vaccines to take advantage of recent vaccine technological advances, such as adenovirus-vectored vaccines and mRNA vaccines, circumventing the potential problems of cytotoxicity associated with 3CD, allowing for the production of immunogenic enterovirus VLPs . The widespread use of vaccines has dramatically reduced global incidence of poliovirus infections over a period of several decades and now the wild-type virus is only endemic in Pakistan and Afghanistan. However, current vaccines require the culture of large quantities of replication-competent virus for their manufacture, thus presenting a potential risk of reintroduction into the environment. It is now widely accepted that vaccination will need to be extended posteradication into the foreseeable future to prevent the potentially catastrophic reintroduction of poliovirus into an immunologically naive population. It is, therefore, imperative that novel vaccines are developed which are not dependent on the growth of live virus for their manufacture. We have expressed stabilized virus-like particles in yeast, from constructs that do not require coexpression of the protease. This is an important step in the development of environmentally safe and commercially viable vaccines against polio, which also provides some intriguing insights into the viral assembly process.
Topics: Humans; Capsid Proteins; Poliovirus; Capsid; Peptide Hydrolases; Antibodies, Viral; Poliomyelitis; Antigens, Viral; Endopeptidases; Enterovirus Infections
PubMed: 36507670
DOI: 10.1128/spectrum.04300-22 -
Journal For Immunotherapy of Cancer Apr 2023Antitumor mechanisms of CD4 T cells remain crudely defined, and means to effectively harness CD4 T-cell help for cancer immunotherapy are lacking. Pre-existing memory...
BACKGROUND
Antitumor mechanisms of CD4 T cells remain crudely defined, and means to effectively harness CD4 T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4 T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy.
METHODS
The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8 T-cell and B-cell knockout, CD4 T-cell depletion, CD4 T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans.
RESULTS
Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4 T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8 T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy.
CONCLUSION
Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4 T-cell help for antitumor CD8 T cells, and implicates eosinophils as antitumor effectors of CD4 T cells.
Topics: Mice; Humans; Animals; CD8-Positive T-Lymphocytes; Eosinophils; CD40 Ligand; Immunity, Innate; Tetanus; Lymphocytes; T-Lymphocytes, Regulatory; Vaccines
PubMed: 37072349
DOI: 10.1136/jitc-2022-006463 -
MMWR. Morbidity and Mortality Weekly... May 2023Since the World Health Assembly established the Global Polio Eradication Initiative (GPEI) in 1988, two of the three wild poliovirus (WPV) serotypes (types 2 and 3) have...
Since the World Health Assembly established the Global Polio Eradication Initiative (GPEI) in 1988, two of the three wild poliovirus (WPV) serotypes (types 2 and 3) have been eradicated, and global WPV cases have decreased by more than 99.9%. Afghanistan and Pakistan remain the only countries where indigenous WPV type 1 (WPV1) transmission has not been interrupted. This report summarizes progress toward global polio eradication during January 1, 2021-March 31, 2023, and updates previous reports (1,2). In 2022, Afghanistan and Pakistan reported 22 WPV1 cases, compared with five in 2021; as of May 5, 2023, a single WPV1 case was reported in Pakistan in 2023. A WPV1 case was reported on the African continent for the first time since 2016, when officials in Malawi confirmed a WPV1 case in a child with paralysis onset in November 2021; neighboring Mozambique subsequently reported eight genetically linked cases. Outbreaks of polio caused by circulating vaccine-derived polioviruses (cVDPVs) can occur when oral poliovirus vaccine (OPV) strains circulate for a prolonged time in underimmunized populations, allowing reversion to neurovirulence (3). A total of 859 cVDPV cases occurred during 2022, an increase of 23% from 698 cases in 2021. cVDPVs were detected in areas where poliovirus transmission had long been eliminated (including in Canada, Israel, the United Kingdom, and the United States). In addition, cocirculation of multiple poliovirus types occurred in multiple countries globally (including Democratic Republic of the Congo [DRC], Israel, Malawi, Mozambique, Republic of the Congo, and Yemen). The 2022-2026 GPEI strategic plan targeted the goal of detecting the last cases of WPV1 and cVDPV in 2023 (4). The current global epidemiology of poliovirus transmission makes the likelihood of meeting this target date unlikely. The detections of poliovirus (WPV1 and cVDPVs) in areas where it had been previously eliminated underscore the threat of continued poliovirus spread to any area where there is insufficient vaccination to poliovirus (3). Mass vaccination and surveillance should be further enhanced in areas of transmission to interrupt poliovirus transmission and to end the global threat of paralytic polio in children.
Topics: Child; Humans; Disease Eradication; Disease Outbreaks; Global Health; Immunization Programs; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Population Surveillance
PubMed: 37167156
DOI: 10.15585/mmwr.mm7219a3 -
Risk Analysis : An Official Publication... Feb 2024Due to the very low, but nonzero, paralysis risks associated with the use of oral poliovirus vaccine (OPV), eradicating poliomyelitis requires ending all OPV use... (Review)
Review
Due to the very low, but nonzero, paralysis risks associated with the use of oral poliovirus vaccine (OPV), eradicating poliomyelitis requires ending all OPV use globally. The Global Polio Eradication Initiative (GPEI) coordinated cessation of Sabin type 2 OPV (OPV2 cessation) in 2016, except for emergency outbreak response. However, as of early 2023, plans for cessation of bivalent OPV (bOPV, containing types 1 and 3 OPV) remain undefined, and OPV2 use for outbreak response continues due to ongoing transmission of type 2 polioviruses and reported type 2 cases. Recent development and use of a genetically stabilized novel type 2 OPV (nOPV2) leads to additional potential vaccine options and increasing complexity in strategies for the polio endgame. Prior applications of integrated global risk, economic, and poliovirus transmission modeling consistent with GPEI strategic plans that preceded OPV2 cessation explored OPV cessation dynamics and the evaluation of options to support globally coordinated risk management efforts. The 2022-2026 GPEI strategic plan highlighted the need for early bOPV cessation planning. We review the published modeling and explore bOPV cessation immunization options as of 2022, assuming that the GPEI partners will not support restart of the use of any OPV type in routine immunization after a globally coordinated cessation of such use. We model the potential consequences of globally coordinating bOPV cessation in 2027, as anticipated in the 2022-2026 GPEI strategic plan. We do not find any options for bOPV cessation likely to succeed without a strategy of bOPV intensification to increase population immunity prior to cessation.
Topics: Humans; Poliovirus Vaccine, Oral; Serogroup; Poliovirus; Poliomyelitis; Poliovirus Vaccine, Inactivated; Global Health; Disease Eradication
PubMed: 37344934
DOI: 10.1111/risa.14158 -
Vaccine Apr 2023
Topics: Humans; Poliovirus; Poliovirus Vaccine, Oral; Poliomyelitis; Vaccination; Disease Outbreaks; Poliovirus Vaccine, Inactivated; Global Health
PubMed: 36907735
DOI: 10.1016/j.vaccine.2023.02.082 -
Journal of Immunological Methods May 2022Next generation poliovirus vaccines are critical to reaching global poliovirus eradication goals. Recent efforts have focused on creating inactivated vaccines using...
Next generation poliovirus vaccines are critical to reaching global poliovirus eradication goals. Recent efforts have focused on creating inactivated vaccines using attenuated Sabin strains that maintain patient safety benefits and immunogenicity of conventional inactivated vaccines while increasing manufacturing safety and lowering production costs, and on developing novel oral vaccines using modified Sabin strains that provide critical mucosal immunity but are further attenuated to minimize risk of reversion to neurovirulence. In addition, there is a push to improve the analytical tools for poliovirus vaccine characterization. Conventional and Sabin inactivated poliovirus vaccines typically rely on standard plate-based ELISA as in vitro D-antigen potency assays in combination with WHO international standards as calibrants. While widely utilized, the current D-antigen ELISA assays have a long time to result (up to 72 h), can suffer from lab-to-lab inconsistency due to non-standardized protocols and reagents, and are inherently singleplex. For D-antigen quantitation, we have developed the VaxArray Polio Assay Kit, a multiplexed, microarray-based immunoassay that uses poliovirus-specific human monoclonal antibodies currently under consideration as standardized reagents for characterizing inactivated Sabin and Salk vaccines. The VaxArray assay can simultaneously quantify all 3 poliovirus serotypes with a time to result of less than 3 h. Here we demonstrate that the assay has limits of quantification suitable for both bioprocess samples and final vaccines, excellent reproducibility and precision, and improved accuracy over an analogous plate-based ELISA. The assay is suitable for adjuvanted combination vaccines, as common vaccine additives and crude matrices do not interfere with quantification, and is intended as a high throughput, standardized quantitation tool to aid inactivated poliovirus vaccine manufacturers in streamlining vaccine development and manufacturing, aiding the global polio eradication effort.
Topics: Antibodies, Viral; Antigens, Viral; Enzyme-Linked Immunosorbent Assay; Humans; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Inactivated; Poliovirus Vaccine, Oral; Reproducibility of Results; Vaccines, Inactivated
PubMed: 35314144
DOI: 10.1016/j.jim.2022.113259 -
Expert Review of Vaccines 2023Hexaxim is a hexavalent vaccine approved as primary and booster vaccination in infants 6 weeks and older, protecting against diphtheria, tetanus, pertussis,... (Review)
Review
INTRODUCTION
Hexaxim is a hexavalent vaccine approved as primary and booster vaccination in infants 6 weeks and older, protecting against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B and Haemophilus influenzae type b.
AREAS COVERED
To evaluate the immunogenicity and reactogenicity (safety) of Hexaxim (Hexyon, Hexacima) in primary and booster vaccine schedules; long-term antibody persistence; concomitant use with other childhood vaccines and use in immunocompromised infants. Hexaxim was found to be noninferior to other licensed hexavalent vaccines, being highly immunogenic for all toxoids/antigens and with an acceptable safety profile. It can be administered concomitantly with other childhood vaccines. Hexaxim can be given as a booster for infants primed with Infanrix Hexa and given in a pentavalent-hexavalent-pentavalent series. Hexaxim elicits a similar immune response and safety profile in human immunodeficiency virus (HIV) positive infants. It has the benefit of being a ready-to-use liquid formulation, minimizing dosage errors and preparation time.
EXPERT OPINION
Hexaxim has an acceptable safety profile and provides immunity against all six targeted diseases. It is an acceptable alternative to other hexavalent vaccines on the market. Further studies are required on the use of immunocompromised patients as well as the antibody persistence of each of the vaccine components.
Topics: Infant; Humans; Child; Immunization, Secondary; Immunization Schedule; Diphtheria-Tetanus-Pertussis Vaccine; Haemophilus Vaccines; Poliovirus Vaccine, Inactivated; Hepatitis B Vaccines; Vaccines, Combined; Antibodies, Bacterial
PubMed: 36545777
DOI: 10.1080/14760584.2023.2161519 -
The Pan African Medical Journal 2023Nigeria made a coordinated effort to be certified by the World Health Organization's African Region for interrupting endemic transmission of wild poliovirus type-1... (Review)
Review
Nigeria made a coordinated effort to be certified by the World Health Organization's African Region for interrupting endemic transmission of wild poliovirus type-1 (WPV1) in August 2020 as a response to the resurgence of WPV1 cases in August 2016 after going two years without a case. The NEOC Data Working Group (DWG) was instrumental in providing quality and timely surveillance and campaign information for decision-making in order to interrupt WPV1 transmission and provide data toward documentation of its elimination for regional certification. The polio pre-campaign dashboard was used to assess the level of preparedness for Oral Poliovirus Vaccine (OPV) polio supplementary immunization activities (SIA) at three weeks, two weeks, one week, and three days to the start of each campaign implemented during 2016-2020. The administrative tally sheet, independent monitoring survey, and Lot Quality Assurance Sampling (LQAS) survey data collected and shared from the implementation level were analyzed by the EOC DWG to provide information by person, place, and time. Using a 90% threshold in LQAS surveys defining quality SIAs, the proportion of Local Government Areas (LGAs) in Nigeria's states in which post-SIA LQAS surveys were conducted that met this threshold were assessed over time. The highest level of preparedness attained by 3 days to a polio campaign during August 2016-February 2020 was 95% and the lowest attained was 77%. The admin, independent monitoring, and LQAS data analysis results were given to EOC working groups for assessing the performance and quality of each campaign. Twenty-twenty five percent of LGAs that failed LQAS were identified for repeat vaccination. Further, acute flaccid paralysis and environmental surveillance data and laboratory results were analyzed and shared with NEOC and partners. The government and partners used the information generated by the Data Working Group to take evidence-based action including determining the scope of the polio campaign, intensification of surveillance and routine immunization activities, and special intervention activities. On average, 12% of the 774 LGAs were identified as polio high risk LGAs for intervention using selected surveillance, routine immunization (RI), SIAs, and other relevant data sets. National Emergency Operation Centre Data Working Group provided quality and timely information that supported decision-making processes for the polio program in Nigeria. The quality and timely information enabled the NEOC to make evidence-based and timely decisions that contributed to gap identification and decision-making.
Topics: Humans; Lot Quality Assurance Sampling; Disease Eradication; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Nigeria; Immunization Programs
PubMed: 38370106
DOI: 10.11604/pamj.supp.2023.45.2.39489 -
MMWR. Morbidity and Mortality Weekly... Jun 2023Since the Global Polio Eradication Initiative (GPEI) was established in 1988, the number of wild poliovirus (WPV) cases has declined by >99.9%, and WPV serotypes 2 and 3...
Since the Global Polio Eradication Initiative (GPEI) was established in 1988, the number of wild poliovirus (WPV) cases has declined by >99.9%, and WPV serotypes 2 and 3 have been declared eradicated (1). By the end of 2022, WPV type 1 (WPV1) transmission remained endemic only in Afghanistan and Pakistan (2,3). However, during 2021-2022, Malawi and Mozambique reported nine WPV1 cases that were genetically linked to Pakistan (4,5), and circulating vaccine-derived poliovirus (cVDPV) outbreaks were detected in 42 countries (6). cVDPVs are oral poliovirus vaccine-derived viruses that can emerge after prolonged circulation in populations with low immunity allowing reversion to neurovirulence and can cause paralysis. Polioviruses are detected primarily through surveillance for acute flaccid paralysis (AFP), and poliovirus is confirmed through stool specimen testing. Environmental surveillance, the systematic sampling of sewage and testing for the presence of poliovirus, supplements AFP surveillance. Both surveillance systems were affected by the COVID-19 pandemic's effects on public health activities during 2020 (7,8) but improved in 2021 (9). This report updates previous reports (7,9) to describe surveillance performance during 2021-2022 in 34 priority countries.* In 2022, a total of 26 (76.5%) priority countries met the two key AFP surveillance performance indicator targets nationally compared with 24 (70.6%) countries in 2021; however, substantial gaps remain in subnational areas. Environmental surveillance expanded to 725 sites in priority countries, a 31.1% increase from the 553 sites reported in 2021. High-quality surveillance is critical to rapidly detect poliovirus transmission and enable prompt poliovirus outbreak response to stop circulation. Frequent monitoring of surveillance guides improvements to achieve progress toward polio eradication.
Topics: Humans; Pandemics; alpha-Fetoproteins; Disease Eradication; Population Surveillance; Global Health; COVID-19; Poliomyelitis; Poliovirus; Enterovirus; Poliovirus Vaccine, Oral; Disease Outbreaks; Immunization Programs
PubMed: 37289657
DOI: 10.15585/mmwr.mm7223a1 -
Medecine Tropicale Et Sante... Jun 2021In 2019, the Central African Republic identified foci of circulating vaccine-derived poliovirus 2 (PVDV2c). The objective of this work is to describe the vaccination...
OBJECTIVE
In 2019, the Central African Republic identified foci of circulating vaccine-derived poliovirus 2 (PVDV2c). The objective of this work is to describe the vaccination status of children paralyzed by PVDV2c and their contacts and to assess the circulation of this strain in these contacts.
PATIENTS AND METHOD
The study population of this retrospective survey consists of children with acute flaccid paralysis (AFP) and their contacts. We included paralyzed children whose sequencing results showed the presence of PVDV2c.
RESULTS
A total of 21 children paralyzed by PVDVc and 64 contacts were enrolled in the survey. Fourteen out of 21 children who are paralyzed (66%) received at least one dose of bivalent oral polio vaccine (OPV) compared to 36 out of 64 contacts (57%, non-significant difference). Of the vaccinated patients, 7 had received less than three doses. For the injectable polio vaccine (IPV), vaccination coverage for both patients and contacts was 33%.The proportion of children who received both doses of OPV and IPV was 33% among patients and 25% in contacts. Contacts with VDPV2 were vaccinated with OPV and IPV, respectively 55 and 27%. VDPV2 and Sabin 2 were also found in contact stools, 34% and 9% respectively.
CONCLUSION
The absence or inadequacy of IPV vaccination has a serious impact on children by the occurrence of virus derived from the vaccine responsible for life-old paralysis. Protecting children from poliomyelitis requires a combination of a good cold chain, multiple doses and adherence to the vaccine schedule.
Topics: Central African Republic; Child; Humans; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Poliovirus Vaccines; Retrospective Studies
PubMed: 35586583
DOI: 10.48327/mtsibulletin.2021.114