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BackgroundUse of oral live-attenuated polio vaccines (OPV), and injected inactivated polio vaccines (IPV) has almost achieved global eradication of wild polio viruses. To address the goals of achieving and maintaining global eradication and minimising the risk of outbreaks of vaccine-derived polioviruses, we tested novel monovalent oral type-2 poliovirus (OPV2) vaccine candidates that are genetically more stable than existing OPVs, with a lower risk of reversion to neurovirulence. Our study represents the first in-human testing of these two novel OPV2 candidates. We aimed to evaluate the safety and immunogenicity of these vaccines, the presence and extent of faecal shedding, and the neurovirulence of shed virus.MethodsIn this double-blind, single-centre phase 1 trial, we isolated participants in a purpose-built containment facility at the University of Antwerp Hospital (Antwerp, Belgium), to minimise the risk of environmental release of the novel OPV2 candidates. Participants, who were recruited by local advertising, were adults (aged 18-50 years) in good health who had previously been vaccinated with IPV, and who would not have any contact with immunosuppressed or unvaccinated people for the duration of faecal shedding at the end of the study. The first participant randomly chose an envelope containing the name of a vaccine candidate, and this determined their allocation; the next 14 participants to be enrolled in the study were sequentially allocated to this group and received the same vaccine. The subsequent 15 participants enrolled after this group were allocated to receive the other vaccine. Participants and the study staff were masked to vaccine groups until the end of the study period. Participants each received a single dose of one vaccine candidate (candidate 1, S2/cre5/S15domV/rec1/hifi3; or candidate 2, S2/S15domV/CpG40), and they were monitored for adverse events, immune responses, and faecal shedding of the vaccine virus for 28 days. Shed virus isolates were tested for the genetic stability of attenuation. The primary outcomes were the incidence and type of serious and severe adverse events, the proportion of participants showing viral shedding in their stools, the time to cessation of viral shedding, the cell culture infective dose of shed virus in virus-positive stools, and a combined index of the prevalence, duration, and quantity of viral shedding in all participants. This study is registered with EudraCT, number 2017-000908-21 and ClinicalTrials.gov, number NCT03430349.FindingsBetween May 22 and Aug 22, 2017, 48 volunteers were screened, of whom 15 (31%) volunteers were excluded for reasons relating to the inclusion or exclusion criteria, three (6%) volunteers were not treated because of restrictions to the number of participants in each group, and 30 (63%) volunteers were sequentially allocated to groups (15 participants per group). Both novel OPV2 candidates were immunogenic and increased the median blood titre of serum neutralising antibodies; all participants were seroprotected after vaccination. Both candidates had acceptable tolerability, and no serious adverse events occurred during the study. However, severe events were reported in six (40%) participants receiving candidate 1 (eight events) and nine (60%) participants receiving candidate 2 (12 events); most of these events were increased blood creatinine phosphokinase but were not accompanied by clinical signs or symptoms. Vaccine virus was detected in the stools of 15 (100%) participants receiving vaccine candidate 1 and 13 (87%) participants receiving vaccine candidate 2. Vaccine poliovirus shedding stopped at a median of 23 days (IQR 15-36) after candidate 1 administration and 12 days (1-23) after candidate 2 administration. Total shedding, described by the estimated median shedding index (50% cell culture infective dose/g), was observed to be greater with candidate 1 than candidate 2 across all participants (2·8 [95% CI 1·8-3·5] vs 1·0 [0·7-1·6]). Reversion to neurovirulence, assessed as paralysis of transgenic mice, was low in isolates from those vaccinated with both candidates, and sequencing of shed virus indicated that there was no loss of attenuation in domain V of the 5'-untranslated region, the primary site of reversion in Sabin OPV.InterpretationWe found that the novel OPV2 candidates were safe and immunogenic in IPV-immunised adults, and our data support the further development of these vaccines to potentially be used for maintaining global eradication of neurovirulent type-2 polioviruses.FundingBill & Melinda Gates Foundation.

In a blinded phase 1 trial (EudraCT 2017-0000908-21; NCT03430349) in Belgium, healthy adults (aged 18-50 years) previously immunized exclusively with inactivated poliovirus vaccine were administered a single dose of 1 of 2 novel type 2 oral poliovirus vaccines (nOPV2-c1: S2/cre5/S15domV/rec1/hifi3 (n = 15); nOPV2-c2: S2/S15domV/CpG40 (n = 15)) and isolated for 28 days in a purpose-built containment facility. Using stool samples collected near days 0, 14, 21, and 28, we evaluated intestinal neutralization and immunoglobulin A responses to the nOPV2s and found that nOPV2-c1 and nOPV2-c2 induced detectable poliovirus type 2-specific intestinal neutralizing responses in 40.0% and 46.7% of participants, respectively. [ABSTRACT FROM AUTHOR]

Background: OVX836 is a recombinant protein vaccine targeting the highly conserved influenza nucleoprotein (NP), which could confer broad-spectrum protection against this disease.Methods: A randomized, placebo-controlled, double-blind, dose-escalating, single- center, first-in-human study was conducted in 36 healthy adults aged 18-49 years. Twelve subjects per cohort (9 vaccine and 3 placebo) received 2 OVX836 intramuscular administrations on days 1 and 28 at the dose level of 30 µg, 90 µg, or 180 µg. Safety and immunogenicity were assessed after each vaccination and for 150 days in total.Results: OVX836 was safe and well tolerated at all dose levels, with no difference in solicited local and systemic symptoms, and unsolicited adverse events between the first and second administration, or between dose levels. All subjects presented pre-existing NP-specific immunity at baseline. OVX836 induced a significant increase in NP-specific interferon-gamma T cells and anti-NP immunoglobulin G at all dose levels after the first vaccination. The second vaccination did not further increase the response. There was a trend for a dose effect in the immune response.Conclusions: The safety and reactogenicity profile, as well as the humoral and cellular immune responses, encourage further evaluation of OVX836 in a larger Phase 2a study. [ABSTRACT FROM AUTHOR]

Background: Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM197 in European adults. Methodology: Following randomized blinded comparison of single vaccination with either Vi-CRM197 or licensed polysaccharide vaccines (both containing 25&midot0 &mgr;g of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM197 (1&midot25 &mgr;g, 5&midot0 mg and 12&midot5 &mgr;g of Vi antigen) with the polysaccharide vaccine. Principal Findings: All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM197 induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM197 formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship. Conclusions: Vi-CRM197 did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia. Trial Registration: ClinicalTrials.gov NCT01123941 NCT01193907 [ABSTRACT FROM AUTHOR]

In 2016, WHO designated Lassa fever a priority disease for epidemic preparedness as part of the WHO Blueprint for Action to Prevent Epidemics. One aspect of preparedness is to promote development of effective medical countermeasures (ie, diagnostics, therapeutics, and vaccines) against Lassa fever. Diagnostic testing for Lassa fever has important limitations and key advancements are needed to ensure rapid and accurate diagnosis. Additionally, the only treatment available for Lassa fever is ribavirin, but controversy exists regarding its effectiveness. Finally, no licensed vaccines are available for the prevention and control of Lassa fever. Ongoing epidemiological and behavioural studies are also crucial in providing actionable information for medical countermeasure development, use, and effectiveness in preventing and treating Lassa fever. This Personal View provides current research priorities for development of Lassa fever medical countermeasures based on literature published primarily in the last 5 years and consensus opinion of 20 subject matter experts with broad experience in public health or the development of diagnostics, therapeutics, and vaccines for Lassa fever. These priorities provide an important framework to ensure that Lassa fever medical countermeasures are developed and readily available for use in endemic and at-risk areas by the end of the decade., Competing Interests: Declaration of interests KAM, AJM, NMM, JTO, MTO, and AKU declare receiving financial support for the completion of this Personal View from Wellcome (grant number 226538/Z/22/Z), payments were made to the University of Minnesota. ADTB is a member of the Vaccine Research, Development and Manufacturing Committee of the Coalition for Epidemic Preparedness Innovations (CEPI). DME is employed by FIND. RFG declares grants U01AI151812, U19AI135995, R01AI132223, R01AI132244, and U19AI142790, all awarded from the National Institute of Allergy and Infectious Diseases, LEAP4WA awarded by the European & Developing Countries Clinical Trials Partnership, and ESEP1904 and INTU1901, both awarded by CEPI; stocks in and royalties or licenses from Zalgen Labs; ownership of a monoclonal antibody patent (WO2018106712A1); and travel support from Wellcome to attend the workshop identified in this Personal View. SG declares financial support for this Personal View from WHO and Wellcome; the receipt of drugs for clinical trials from Toyama–Fujifilm; grants (all payments were made to SG's institutions) from the German Research Foundation (grants GU 883/4-2, GU 883/5-1, and GU 883/7-1), the European Commission (project 101103204—INTEGRATE), the German Government, Ministry of Health (projects ZMI1-2521WHO002 and ZMII2-2523GHP006), CEPI (framework agreement for implementing partner services); the Kirmser Foundation (donation of equipment); speaker honoraria for continuing medical education on viral haemorrhagic fevers; and support for attending meetings from WHO, Wellcome, and CEPI, including travel support from Wellcome to attend the workshop identified in this Personal View. LTM declares being a science consultant at FIND, for which she receives grants, contracts, and consulting fees; and travel support from Wellcome to attend the workshop identified in this Personal View. SAO declares a consulting contract with CEPI (payments made to SAO); is a member of the INTEGRATE consortium with grants from the European & Developing Countries Clinical Trials Partnership (payments made to SAO's institution); and support from CEPI and EDCTP funds (payments made to travel agencies and through SAO's institution). CR declares participation on a Data Safety Monitoring Board or Advisory Board (this advisory board was designated after CR's participation in the work leading to this Personal View). WKA is Executive Director of the African Vaccine Manufacturing Initiative, and Cheif Executive of National Vaccine Institute, Ghana. DAA, IMA, WKA, ADTB, DGB, EF-C, IdC, DSG, SBG, MJ, KAM, JTO, MTO, AKU, and CSS declare Wellcome supported for travel to attend the workshop identified in this Personal View. PCF, PJH, and JPG worked at Wellcome during the time that this Personal View was completed. All other authors declare no competing interests. No authors were paid by a pharmaceutical company or any other agency to write this Personal View. The authors alone are responsible for the views expressed in this Personal View and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)