Novel Oral Polio Vaccine Type 2 Use for Polio Outbreak Response: A Global Effort for a Global Health Emergency.

A sharp rise in circulating vaccine-derived poliovirus type 2 (cVDPV2) outbreaks in the years following the cessation of routine use of poliovirus type 2-containing oral polio vaccine and the trend of seeding new emergences with suboptimal vaccination response during the same time-period led to the accelerated development of the novel oral polio vaccine type 2 (nOPV2), a vaccine with enhanced genetic stability and lower likelihood of reversion to neuroparalytic variants compared to its Sabin counterpart. In November 2020, nOPV2 became the first vaccine to be granted an Emergency Use Listing (EUL) by the World Health Organization (WHO) Prequalification Team (PQT), allowing close to a billion doses to be used by countries within three years after its first rollout and leading to full licensure and WHO prequalification (PQ) in December 2023. The nOPV2 development process exemplifies how scientific advances and innovative tools can be applied to combat global health emergencies in an urgent and adaptive way, building on a collaborative effort among scientific, regulatory and implementation partners and policymakers across the globe.

Safety of the novel oral poliovirus vaccine type 2 (nOPV2) in infants and young children aged 1 to <5 years and lot-to-lot consistency of the immune response to nOPV2 in infants in The Gambia: a phase 3, double-blind, randomised controlled trial.

Background: Novel oral poliovirus vaccine type 2 (nOPV2) has been engineered to improve the genetic stability of Sabin oral poliovirus vaccine (OPV) and reduce the emergence of circulating vaccine-derived polioviruses. This trial aimed to provide key safety and immunogenicity data required for nOPV2 licensure and WHO prequalification.

Methods: This phase 3 trial recruited infants aged 18 to <52 weeks and young children aged 1 to <5 years in The Gambia.

Safety and immunogenicity of shorter interval schedules of the novel oral poliovirus vaccine type 2 in infants: a phase 3, randomised, controlled, non-inferiority study in the Dominican Republic.

Background: The novel oral poliovirus vaccine type 2 (nOPV2) is now authorised by a WHO emergency use listing and widely distributed to interrupt outbreaks of circulating vaccine-derived poliovirus type 2. As protection of vulnerable populations, particularly young infants, could be facilitated by shorter intervals between the two recommended doses, we aimed to assess safety and non-inferiority of immunogenicity of nOPV2 in 1-week, 2-week, and 4-week schedules.

Methods: In this phase 3, open-label, randomised trial, healthy, full-term, infants aged 6-8 weeks from a hospital or a clinic in the Dominican Republic were randomly allocated (1:1:1 ratio) using a pre-prepared, computer-generated randomisation schedule to three groups to receive two doses of nOPV2 immunisations with a 1-week interval (group A), 2-week interval (group B), or 4-week interval (group C).

Safety, tolerability, and immunogenicity of inactivated poliovirus vaccine with or without E.coli double mutant heat-labile toxin (dmLT) adjuvant in healthy adults; a phase 1 randomized study.

Background: Inactivated trivalent poliovirus vaccine (IPV) induces humoral immunity, which protects against paralytic poliomyelitis but does not induce sufficient mucosal immunity to block intestinal infection. We assessed the intestinal immunity in healthy adults in Belgium conferred by a co-formulation of IPV with the mucosal adjuvant double mutant Labile Toxin (dmLT) derived from Escherichia coli.

Methods: Healthy fully IPV-vaccinated 18-45-year-olds were randomly allocated to three groups: on Day 1 two groups received one full dose of IPV (n = 30) or IPV + dmLT (n = 30) in a blinded manner, and the third received an open-label dose of bivalent live oral polio vaccine (bOPV types 1 and 3, n = 20).

Enabling accelerated vaccine roll-out for Public Health Emergencies of International Concern (PHEICs): Novel Oral Polio Vaccine type 2 (nOPV2) experience.

To address the evolving risk of circulating vaccine-derived poliovirus type 2 (cVDPV2), Global Polio Eradication Initiative (GPEI) partners are working closely with countries to deploy an additional innovative tool for outbreak response - novel oral polio vaccine type 2 (nOPV2). The World Health Organization's (WHO) Prequalification program issued an Emergency Use Listing (EUL) recommendation for nOPV2 on 13 November 2020. The WHO's EUL procedure was created to assess and list unlicensed vaccines, therapeutics and diagnostics to enable their use in response to a Public Health Emergency of International Concern (PHEIC).

Cooperation Between Systemic and Mucosal Antibodies Induced by Virosomal Vaccines Targeting HIV-1 Env: Protection of Indian Rhesus Macaques Against Low-Dose Intravaginal SHIV Challenges.

A virosomal vaccine inducing systemic/mucosal anti-HIV-1 gp41 IgG/IgA had previously protected Chinese-origin rhesus macaques (RMs) against vaginal SHIV challenges. Here, we assessed its efficacy in Indian-origin RMs by intramuscular priming/intranasal boosting (n=12/group). Group K received virosome-P1-peptide alone (harboring the Membrane Proximal External Region), Group L combined virosome-rgp41 plus virosome-P1, and Group M placebo virosomes.

Evaluating stability of attenuated Sabin and two novel type 2 oral poliovirus vaccines in children.

Novel oral poliovirus vaccine type 2 (nOPV2) is being developed to reduce the rare occurrence of disease and outbreaks associated with the genetic instability of the Sabin vaccine strains. Children aged 1 to 5 years were enrolled in two related clinical studies to assess safety, immunogenicity, shedding rates and properties of the shed virus following vaccination with nOPV2 (two candidates) versus traditional Sabin OPV type 2 (mOPV2). The anticipated pattern of reversion and increased virulence was observed for shed Sabin-2 virus, as assessed using a mouse model of poliovirus neurovirulence.

Model Systems to Study the Chronic, Polymicrobial Infections in Cystic Fibrosis: Current Approaches and Exploring Future Directions.

A recent workshop titled "Developing Models to Study Polymicrobial Infections," sponsored by the Dartmouth Cystic Fibrosis Center (DartCF), explored the development of new models to study the polymicrobial infections associated with the airways of persons with cystic fibrosis (CF). The workshop gathered 35+ investigators over two virtual sessions. Here, we present the findings of this workshop, summarize some of the challenges involved with developing such models, and suggest three frameworks to tackle this complex problem.

Assessment of genetic changes and neurovirulence of shed Sabin and novel type 2 oral polio vaccine viruses.

Sabin-strain oral polio vaccines (OPV) can, in rare instances, cause disease in recipients and susceptible contacts or evolve to become circulating vaccine-derived strains with the potential to cause outbreaks. Two novel type 2 OPV (nOPV2) candidates were designed to stabilize the genome against the rapid reversion that is observed following vaccination with Sabin OPV type 2 (mOPV2). Next-generation sequencing and a modified transgenic mouse neurovirulence test were applied to shed nOPV2 viruses from phase 1 and 2 studies and shed mOPV2 from a phase 4 study.

Intestinal Antibody Responses to 2 Novel Live Attenuated Type 2 Oral Poliovirus Vaccines in Healthy Adults in Belgium.

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.

Safety and immunogenicity of inactivated poliovirus vaccine schedules for the post-eradication era: a randomised open-label, multicentre, phase 3, non-inferiority trial.

Background: Following the global eradication of wild poliovirus, countries using live attenuated oral poliovirus vaccines will transition to exclusive use of inactivated poliovirus vaccine (IPV) or fractional doses of IPV (f-IPV; a f-IPV dose is one-fifth of a normal IPV dose), but IPV supply and cost constraints will necessitate dose-sparing strategies. We compared immunisation schedules of f-IPV and IPV to inform the choice of optimal post-eradication schedule.

Methods: This randomised open-label, multicentre, phase 3, non-inferiority trial was done at two centres in Panama and one in the Dominican Republic.

A Randomized Phase 4 Study of Immunogenicity and Safety After Monovalent Oral Type 2 Sabin Poliovirus Vaccine Challenge in Children Vaccinated with Inactivated Poliovirus Vaccine in Lithuania.

Background: Understanding immunogenicity and safety of monovalent type 2 oral poliovirus vaccine (mOPV2) in inactivated poliovirus vaccine (IPV)-immunized children is of major importance in informing global policy to control circulating vaccine-derived poliovirus outbreaks.

Methods: In this open-label, phase 4 study (NCT02582255) in 100 IPV-vaccinated Lithuanian 1-5-year-olds, we measured humoral and intestinal type 2 polio neutralizing antibodies before and 28 days after 1 or 2 mOPV2 doses given 28 days apart and measured stool viral shedding after each dose. Parents recorded solicited adverse events (AEs) for 7 days after each dose and unsolicited AEs for 6 weeks after vaccination.

Impact of Maternal Antibody on the Immunogenicity of Inactivated Polio Vaccine in Infants Immunized With Bivalent Oral Polio Vaccine: Implications for the Polio Eradication Endgame.

Background: Quantifying interference of maternal antibodies with immune responses to varying dose schedules of inactivated polio vaccine (IPV) is important for the polio endgame as IPV replaces oral polio vaccine (OPV).

Methods: Type 2 poliovirus humoral and intestinal responses were analyzed using pre-IPV type 2 seropositivity as proxy for maternal antibodies from 2 trials in Latin America. Infants received 1 or 2 doses of IPV in sequential IPV-bivalent oral polio vaccine (bOPV) or mixed bOPV-IPV schedules.

Immunogenicity of New Primary Immunization Schedules With Inactivated Poliovirus Vaccine and Bivalent Oral Polio Vaccine for the Polio Endgame: A Review.

In May 2016, countries using oral polio vaccine for routine immunization switched from trivalent oral poliovirus vaccine (tOPV) to bivalent type 1 and 3 OPV (bOPV). This was done in order to reduce risks from type 2 vaccine-derived polioviruses (VDPV2) and vaccine-associated paralytic poliomyelitis (VAPP) and to introduce ≥1 dose of inactivated poliovirus vaccine (IPV) to mitigate post-switch loss of type 2 immunity. We conducted a literature review of studies that assessed humoral and intestinal immunogenicity induced by the newly recommended schedules.

Exploring the relationship between polio type 2 serum neutralizing antibodies and intestinal immunity using data from two randomized controlled trials of new bOPV-IPV immunization schedules.

Background: Inactivated polio vaccine (IPV) is now the only source of routine type 2 protection. The relationship, if any, between vaccine-induced type 2 humoral and intestinal immunity is poorly understood.

Methods: Two clinical trials in five Latin American countries of mixed or sequential bOPV-IPV schedules in 1640 infants provided data on serum neutralizing antibodies (NAb) and intestinal immunity, assessed as viral shedding following oral mOPV2 challenge.

Vaccine-induced mucosal immunity to poliovirus: analysis of cohorts from an open-label, randomised controlled trial in Latin American infants.

Background: Identification of mechanisms that limit poliovirus replication is crucial for informing decisions aimed at global polio eradication. Studies of mucosal immunity induced by oral poliovirus (OPV) or inactivated poliovirus (IPV) vaccines and mixed schedules thereof will determine the effectiveness of different vaccine strategies to block virus shedding. We used samples from a clinical trial of different vaccination schedules to measure intestinal immunity as judged by neutralisation of virus and virus-specific IgA in stools.

Rotavirus Serum IgA Immune Response in Children Receiving Rotarix Coadministered With bOPV or IPV.

Background: Vaccine schedules including bivalent oral and inactivated poliovirus vaccines will replace trivalent oral poliovirus vaccines in 2016.

Methods: We evaluated rotavirus immunoglobulin A seroresponses when the second dose of Rotarix at 16 weeks was given concomitantly with inactivated or bivalent oral poliovirus vaccines.

Results: Rotavirus immunoglobulin A seroresponse rate at week 28 was 15% lower in recipients of bivalent oral poliovirus vaccines compared with inactivated poliovirus vaccines.

Humoral and intestinal immunity induced by new schedules of bivalent oral poliovirus vaccine and one or two doses of inactivated poliovirus vaccine in Latin American infants: an open-label randomised controlled trial.

Background: Replacement of the trivalent oral poliovirus vaccine (tOPV) with bivalent types 1 and 3 oral poliovirus vaccine (bOPV) and global introduction of inactivated poliovirus vaccine (IPV) are major steps in the polio endgame strategy. In this study, we assessed humoral and intestinal immunity in Latin American infants after three doses of bOPV combined with zero, one, or two doses of IPV.

Methods: This open-label randomised controlled multicentre trial was part of a larger study.

Hospital resource utilization with doripenem versus imipenem in the treatment of ventilator-associated pneumonia.

Background: Ventilator-associated pneumonia (VAP) is a common nosocomial infection that is associated with prolonged length of stay (LOS) and significant mortality.

Objective: The aim of this study was to compare resource utilization with doripenem, an investigational carbapenem, versus imipenem from a hospital perspective among patients with VAP.

Methods: This analysis was based on data from a Phase III, randomized, open-label, noninferiority study that compared clinical cure of VAP with doripenem 500 mg q8h i.