Development of multidose thermotolerant formulations of a vector-based Covid-19 vaccine candidate, NDV-HXP-S in different product formats: Stability and preservative efficacy study.

Current lead coronavirus vaccines require continuous cold or ultra-cold storage from the manufacturing site to the field to maintain protective efficacy. Since cold chain capacity is limited and complex, logistics planning is crucial to limit vaccine wastage.[1] The restrictive storage concerns also make it difficult to share vaccines between public health departments and neighboring states, leading to increased vaccine wastage.

Application of MPBT Assay for Multiplex Determination of Infectious Titers and for Selection of the Optimal Formulation for the Trivalent Novel Oral Poliovirus Vaccine.

Recently, a multiplex PCR-based titration (MPBT) assay was developed for simultaneous determination of infectious titers of all three Sabin strains of the oral poliovirus vaccine (OPV) to replace the conventional CCID assay, which is both time-consuming and laborious. The MPBT assay was shown to be reproducible, robust and sensitive. The conventional and MPBT assays showed similar results and sensitivity.

Development of a quantitative ELISA for SARS-CoV-2 vaccine candidate, NDV-HXP-S, with CpG 1018® adjuvant.

NDV-HXP-S is a Newcastle disease virus (NDV) vectored vaccine candidate which expresses the S-antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This vaccine candidate is under evaluation in human clinical studies with and without cytosine phosphate guanine (CpG) 1018® adjuvant. Existing potency methods for NDV-HXP-S do not allow for quantification of the S-antigen when the adjuvant is present.

Preclinical Safety and Pharmacokinetics of Heat Stable Oxytocin in Sublingual Fast-Dissolving Tablet Formulation.

The work reported here focuses on an evaluation of a novel heat stable formulation of a uterotonic peptide drug oxytocin involving stability testing under elevated temperatures and toxicokinetic response generated by sublingual (SL) administration in rabbits. The formulation was thermotolerant, maintaining the potency of oxytocin in the form of a fast-dissolving tablet at the end of 2-year storage at 30 °C/65% relative humidity with less than 5% loss in oxytocin content based on analytical high performance liquid chromatography (HPLC). The toxicokinetic results in rabbits showed that the fast-dissolving tablet was safe without any reactogenicity or toxicity associated with SL administration or the excipients present in the formulation.

Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam.

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus (NDV) vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1. The spike protein was stabilized and incorporated into NDV virions by removing the polybasic furin cleavage site, introducing the transmembrane domain and cytoplasmic tail of the fusion protein of NDV, and introducing six prolines for stabilization in the prefusion state.

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial.

Background: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed by public sector manufacturers in Thailand, Vietnam, and Brazil; herein are initial results from Thailand.

Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: Interim Results of a Randomised, Placebo-Controlled, Phase 1/2 Trial.

Background: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed in Thailand, Vietnam, and Brazil; herein are initial results from Thailand.

Feasibility Study for the Rectal Route of Administration for Gentamicin Evaluated in the Neonatal Minipig Model.

Neonatal infections are a major cause of newborn mortality in low- and middle-income countries, particularly in areas without access to inpatient care. To address this, the World Health Organization developed guidelines for delivering simplified antibiotic regimens (oral amoxicillin and intramuscular gentamicin) in outpatient settings to young infants with suspected serious bacterial infection when referral is not feasible. However, there are still limitations to access, as the regimen requires a health care provider trained in giving intramuscular injections to infants.

Technical product attributes in development of an oral enteric vaccine for infants.

Development of an oral enteric vaccine for infants is important for Shigella and enterotoxigenic Escherichia coli (ETEC) vaccine development. At a recent workshop titled "Technical Product Attributes in Development of an Oral Enteric Vaccine for Infants," at the 2nd International Vaccines Against Shigella and ETEC Conference (VASE Conference), the preferred product attributes for development were discussed for these vaccines. The aims of this workshop were to identify gaps and gather opinions from key experts from preclinical, process development, manufacturing, regulatory, and clinical areas to fine-tune and refine key target product attributes for infant oral vaccine development.

Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro.

Development of a Vaginal Fast-Dissolving Insert Combining Griffithsin and Carrageenan for Potential Use Against Sexually Transmitted Infections.

Precoital, on-demand topical microbicides to reduce a woman's risk of sexually transmitted infections have been in development for nearly 3 decades, but no product has been approved due to acceptability issues and poor adherence in clinical trials. We set out to develop a self-administered vaginal fast-dissolving insert (FDI) produced by freeze-drying that would deliver safe and effective amounts of the antiviral agents griffithsin (GRFT) and carrageenan (CG) and would have properties women and their partners find acceptable. We evaluated FDI physical criteria, attributes of the gel produced upon dissolving, and GRFT stability.

The Palatability of Lopinavir and Ritonavir Delivered by an Innovative Freeze-Dried Fast-Dissolving Tablet Formulation.

Negative hedonic sensory qualities of HIV antiretroviral drugs often reduce patient adherence particularly in pediatric populations requiring oral consumption. This study examines the palatability of an innovative delivery mechanism utilizing a freeze-drying-in-blister approach to create fast-dissolving tablets (FDTs) containing a fixed-dose combination of lopinavir and ritonavir (LPV/r). Consumption patterns of solutions during brief-access and long-term testing and baby foodstuff consumption were analyzed to evaluate the orosensory detection and avoidance of placebo FDTs containing no LPV/r (FDT-) and FDTs containing LPV/r (FDT+).

Heat-stable sublingual oxytocin tablets as a potential needle-free approach for preventing postpartum hemorrhage in low-resource settings.

Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; however, oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free administration.

Preformulation studies with the Escherichia coli double mutant heat-labile toxin adjuvant for use in an oral vaccine.

Double mutant heat-labile toxin (dmLT) is a promising adjuvant for oral vaccine administration. The aims of our study were to develop sensitive methods to detect low concentrations of dmLT and to use the assays in preformulation studies to determine whether dmLT remains stable under conditions encountered by an oral vaccine. We developed a sandwich ELISA specific for intact dmLT and a sensitive SDS-PAGE densitometry method, and tested stability of dmLT in glass and plastic containers, in saliva, at the pH of stomach fluid, and in high-osmolarity buffers.

Developing a Flexible Pediatric Dosage Form for Antiretroviral Therapy: A Fast-Dissolving Tablet.

Current presentations of the anti-HIV drugs lopinavir and ritonavir make appropriate dosing for children difficult. We conducted a feasibility study to develop a formulation for these drugs with child-safe excipients in a flexible dosage form for children across the pediatric age spectrum. The freeze-drying in blister approach was used to produce fast-dissolving tablets (FDTs), as these can be dispersed in fluids for easy administration, even to infants, and appropriate portions of the dispersion can be given for different ages/weights.

Presentation matters: Buffers, packaging, and delivery devices for new, oral enteric vaccines for infants.

Oral administration of vaccines is simpler and more acceptable than injection via needle and syringe, particularly for infants (Fig. 1) This route is promising for new vaccines in development against enterotoxigenic Escherichia coli (ETEC) and Shigella that cause childhood diarrhea with devastating consequences in low-resource countries. However, vaccine antigens and adjuvants given orally need buffering against the degradative effects of low stomach pH, and the type and volume of antacid buffer require special attention for infants.

Preparing an Adjuvanted Thermoresponsive Gel Formulation for Sublingual Vaccination.

Thermoresponsive gels have unique physicochemical properties that may enable more effective mucosal delivery of active compounds. The thermoresponsive gel (TRG) formulation developed by our group for sublingual delivery maintains fluid-like liquid properties at 2 °C-8 °C and forms a gel at the physiological temperature (~37 °C) within a few seconds. Here, we describe the preparation of a thermoresponsive gel vaccine formulation.

Stability of live attenuated rotavirus vaccine with selected preservatives and primary containers.

Rotavirus infection, which can be prevented by vaccination, is responsible for a high burden of acute gastroenteritis disease in children, especially in low-income countries. An appropriate formulation, packaging, and delivery device for oral rotavirus vaccine has the potential to reduce the manufacturing cost of the vaccine and the logistical impact associated with introduction of a new vaccine, simplify the vaccination procedure, and ensure that the vaccine is safely and accurately delivered to children. Single-dose prefilled presentations can be easy to use; however, they are typically more expensive, can be a bottleneck during production, and occupy a greater volume per dose vis-à-vis supply chain storage and medical waste disposal, which is a challenge in low-resource settings.

A study of different buffers to maximize viability of an oral Shigella vaccine.

Live, whole cell killed and subunit vaccines are being developed for diarrheal diseases caused by V. cholerae, Shigella species, ETEC, and Campylobacter. Some of these vaccines can be administered orally since this route best mimics natural infection.

Serum and mucosal antibody responses to inactivated polio vaccine after sublingual immunization using a thermoresponsive gel delivery system.

Administering vaccines directly to mucosal surfaces can induce both serum and mucosal immune responses. Mucosal responses may prevent establishment of initial infection at the port of entry and subsequent dissemination to other sites. The sublingual route is attractive for mucosal vaccination, but both a safe, potent adjuvant and a novel formulation are needed to achieve an adequate immune response.

Stabilization of HAC1 influenza vaccine by spray drying: formulation development and process scale-up.

Purpose: Stable vaccines with long shelf lives and reduced dependency on the cold chain are ideal for stockpiling and rapid deployment during public emergencies, including pandemics. Spray drying is a low-cost process that has potential to produce vaccines stable at a wide range of temperatures. Our aim was to develop a stable formulation of a recombinant H1N1 influenza hemagglutinin vaccine candidate and take it to pilot-scale spray-drying production.

Development of a fast-dissolving tablet formulation of a live attenuated enterotoxigenic E. coli vaccine candidate.

Vaccination is considered the most cost-effective approach to preventing infectious diseases, yet better formulations and delivery methods for efficient distribution and administration of vaccines are needed, especially for low-resource settings. A fast-dissolving tablet (FDT) that could be packaged in a compact stackable blister sheet is a potentially attractive option for formulating oral vaccines, since it would minimally impact the cold chain and could potentially be administered directly to patients without reconstitution. This study focused on using one component of a live attenuated trivalent vaccine under development to produce a FDT for the prevention of diarrhea induced by enterotoxigenic Escherichia coli (ETEC).

Characterization of a thermostable hepatitis B vaccine formulation.

Cold chain requirements for vaccine storage and distribution are both economic and logistical burdens for immunization programs, especially those in lower-resource settings. Inadvertent exposure of vaccines to both heat and freezing temperatures within such cold chains are frequently occurring problems in both developing and industrialized countries. Here we report on a new hepatitis B vaccine formulation that is stable against repeated freezing at -20 degrees C and is also stable for 12 months at 37 degrees C.