An introduction to the Marburg virus vaccine consortium, MARVAC.

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.

Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines-Selecting Compounds for Clinical Evaluation in Coronavirus Disease 2019 Clinical Trials.

Given the urgent need for coronavirus disease 2019 therapeutics, early in the pandemic the Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership rapidly designed a unique therapeutic agent intake and assessment process for candidate treatments of coronavirus disease 2019. These treatments included antivirals, immune modulators, severe acute respiratory syndrome coronavirus 2 neutralizing antibodies, and organ-supportive treatments at both the preclinical and clinical stages of development. The ACTIV Therapeutics-Clinical Working Group Agent Prioritization subgroup established a uniform data collection process required to perform an assessment of any agent type using review criteria that were identified and differentially weighted for each agent class. The ACTIV Therapeutics-Clinical Working Group evaluated over 750 therapeutic agents with potential application for coronavirus disease 2019 and prioritized promising candidates for testing within the master protocols conducted by ACTIV. In addition, promising agents among preclinical candidates were selected by ACTIV to be matched with laboratories that could assist in executing rigorous preclinical studies. Between April 14, 2020, and May 31, 2021, the Agent Prioritization subgroup advanced 20 agents into the Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines master protocols and matched 25 agents with laboratories to assist with preclinical testing.

Digital health technology used in emergency large-scale vaccination campaigns in low- and middle-income countries: a narrative review for improved pandemic preparedness.

INTRODUCTION: Large-scale vaccination campaigns can benefit from using digital health tools, particularly in low- and middle-income countries (LMICs). Selecting the best tool to fit into a pre-existing digital landscape can be challenging. AREAS COVERED: We conducted a narrative review in PubMed and the grey literature for data available within 5 years to provide an overview of digital health tools used in large-scale vaccination campaigns for outbreak response in LMICs. We discuss tools used along the typical steps of a vaccination process. Digital tool functionalities and technical specifications, open-source options, data privacy and security concerns, and lessons learned from the use of these tools are discussed. EXPERT OPINION: The landscape of digital health tools for large-scale vaccination processes in LMICs is growing. For efficient implementation, countries should prioritize the appropriate tool(s) depending on their needs and available resources, develop a robust framework around data privacy and security, and select sustainable features. Improving internet connectivity and digital literacy in LMICs will facilitate adoption. This review may aid LMICs still needing to prepare large-scale vaccination campaigns in the selection of supporting digital health tools. Further research on impact and cost-effectiveness is needed.

A pan-serotype antiviral to prevent and treat dengue: A journey from discovery to clinical development driven by public-private partnerships.

While progress has been made in fighting diseases disproportionally affecting underserved populations, unmet medical needs persist for many neglected tropical diseases. The World Health Organization has encouraged strong public-private partnerships to address this issue and several public and private organizations have set an example in the past showing a strong commitment to combat these diseases. Pharmaceutical companies are contributing in different ways to address the imbalance in research efforts. With this review, we exemplify the role of a public-private partnership in research and development by the journey of our dengue antiviral molecule that is now in early clinical development. We detail the different steps of drug development and outline the contribution of each partner to this process. Years of intensive collaboration resulted in the identification of two antiviral compounds, JNJ-A07 and JNJ-1802, the latter of which has advanced to clinical development.

The NIH-led research response to COVID-19.

Investment, collaboration, and coordination have been key.

DNA vaccination in rhesus macaques induces potent immune responses and decreases acute and chronic viremia after SIVmac251 challenge.

Optimized plasmid DNAs encoding the majority of SIVmac239 proteins and delivered by electroporation (EP) elicited strong immune responses in rhesus macaques. Vaccination decreased viremia in both the acute and chronic phases of infection after challenge with pathogenic SIVmac251. Two groups of macaques were vaccinated with DNA plasmids producing different antigen forms, "native" and "modified," inducing distinct immune responses. Both groups showed significantly lower viremia during the acute phase of infection, whereas the group immunized with the native antigens showed better protection during the chronic phase (1.7 log decrease in virus load, P = 0.009). Both groups developed strong cellular and humoral responses against the DNA vaccine antigens, which included Gag, Pol, Env, Nef, and Tat. Vaccination induced both central memory and effector memory T cells that were maintained at the day of challenge, suggesting the potential for rapid mobilization upon virus challenge. The group receiving the native antigens developed higher and more durable anti-Env antibodies, including neutralizing antibodies at the day of challenge. These results demonstrate that DNA vaccination in the absence of any heterologous boost can provide protection from high viremia comparable to any other vaccine modalities tested in this macaque model.

Multivalent smallpox DNA vaccine delivered by intradermal electroporation drives protective immunity in nonhuman primates against lethal monkeypox challenge.

The threat of a smallpox-based bioterrorist event or a human monkeypox outbreak has heightened the importance of new, safe vaccine approaches for these pathogens to complement older poxviral vaccine platforms. As poxviruses are large, complex viruses, they present technological challenges for simple recombinant vaccine development where a multicomponent mixtures of vaccine antigens are likely important in protection. We report that a synthetic, multivalent, highly concentrated, DNA vaccine delivered by a minimally invasive, novel skin electroporation microarray can drive polyvalent immunity in macaques, and offers protection from a highly pathogenic monkeypox challenge. Such a diverse, high-titer antibody response produced against 8 different DNA-encoded antigens delivered simultaneously in microvolumes has not been previously described. These studies represent a significant improvement in the efficiency of the DNA vaccine platform, resulting in immune responses that mimic live viral infections, and would likely have relevance for vaccine design against complex human and animal pathogens.

A comparison of the growth responses following intramuscular GHRH plasmid administration versus daily growth hormone injections in young pigs.

The efficacy of daily porcine growth hormone (GH) injections versus plasmid-driven porcine GH-releasing hormone (pGHRH) production to promote growth was assessed. Ten-day-old piglets were injected intramuscularly with 0.1, 1, or 3 mg pGHRH, or a control plasmid followed by electroporation. Plasmid constructs were driven by a synthetic muscle-specific promoter. A fifth group received daily injections of GH [0.15 mg/(kg.day)]. Control and pGHRH-treated pigs were pair-fed to GH-treated pigs. Body composition was assessed by dual-energy X-ray absorptiometry (DXA). Weight gains of GH- and pGHRH-treated pigs were greater than of controls (P < 0.001) due to greater lean mass accretion; fat accretion was similar across all treatments. Weight gain of pGHRH- and GH-treated pigs was similar for 6 weeks, but over the final 10 days, only pigs administered the highest plasmid dose maintained higher growth rates. Serum insulin-like growth factor-I (IGF-I) levels were two- to threefold higher in GH- and pGHRH-treated pigs than in controls after 4 weeks (P = 0.05), but subsequently decreased to control levels in the pGHRH-treated group. Organ weights were greater in GH- than pGHRH-treated and control piglets (P < 0.02). These results demonstrate that pGHRH transfer is effective for promoting growth and avoids the need for the frequent injections necessitated with peptide hormone use.

Comparative analysis of immune responses induced by vaccination with SIV antigens by recombinant Ad5 vector or plasmid DNA in rhesus macaques.

DNA vaccines have undergone important enhancements in their design, formulation, and delivery process. Past literature supports that DNA vaccines are not as immunogenic in nonhuman primates as live vector systems. The most potent recombinant vector system for induction of cellular immune responses in macaques and humans is adenovirus serotype 5 (Ad5), an important benchmark for new vaccine development. Here, we performed a head-to-head evaluation of the Merck Ad5 SIV vaccine and an optimized electroporation (EP) delivered SIV DNA vaccine in macaques. Animals receiving the Ad5 vaccine were immunized three times, whereas the DNA-vaccinated animals were immunized up to four times based on optimized protocols. We observed significant differences in the quantity of IFNgamma responses by enzyme-linked immunosorbent spot (ELISpot), greater proliferative capacity of CD8(+) T cells, and increased polyfunctionality of both CD4(+) and CD8(+) T cells in the DNA-vaccinated group. Importantly, Ad5 immunizations failed to boost following the first immunization, whereas DNA responses were continually boosted with all four immunizations demonstrating a major advantage of these improved DNA vaccines. These optimized DNA vaccines induce very different immune phenotypes than traditional Ad5 vaccines, suggesting that they could play an important role in vaccine research and development.

Electroporation of synthetic DNA antigens offers protection in nonhuman primates challenged with highly pathogenic avian influenza virus.

Avian influenza highlights the need for novel vaccination techniques that would allow for the rapid design and production of safe and effective vaccines. An ideal platform would be capable of inducing both protective antibodies and potent cellular immune responses. These potential advantages of DNA vaccines remain unrealized due to a lack of efficacy in large animal studies and in human trials. Questions remain regarding the potential utility of cellular immune responses against influenza virus in primates. In this study, by construct optimization and in vivo electroporation of synthetic DNA-encoded antigens, we observed the induction of cross-reactive cellular and humoral immune responses individually capable of providing protection from influenza virus infection in the rhesus macaque. These studies advance the DNA vaccine field and provide a novel, more tolerable vaccine with broad immunogenicity to avian influenza virus. This approach appears important for further investigation, including studies with humans.

Electroporation for the delivery of DNA-based vaccines and immunotherapeutics: current clinical developments.

Electroporation (EP) has been used in basic research for the past 25 years to aid in the transfer of DNA into cells in vitro. EP in vivo enhances transfer of DNA vaccines and therapeutic plasmids to the skin, muscle, tumors, and other tissues resulting in high levels of expression, often with serological and clinical benefits. The recent interest in nonviral gene transfer as treatment options for a vast array of conditions has resulted in the refinement and optimization of EP technology. Current research has revealed that EP can be successfully used in many species, including humans. Clinical trials are currently under way. Herein, the transition of EP from basic science to clinical trials will be discussed.

Gene therapy by electroporation for the treatment of chronic renal failure in companion animals.

BACKGROUND: Growth hormone-releasing hormone (GHRH) plasmid-based therapy for the treatment of chronic renal failure and its complications was examined. Companion dogs (13.1+/-0.8 years, 29.4+/-5.01 kg) and cats (13.2+/-0.9 years, 8.5+/-0.37 kg) received a single 0.4 mg or 0.1 mg species-specific plasmid injection, respectively, intramuscularly followed by electroporation, and analyzed up to 75 days post-treatment; controls underwent electroporation without plasmid administration. RESULTS: Plasmid-treated animals showed an increase in body weight (dogs 22.5% and cats 3.2%) compared to control animals, and displayed improved quality of life parameters including significant increases in appetite, activity, mentation and exercise tolerance levels. Insulin-like growth factor I (IGF-I, the downstream effector of GHRH) levels were increased in the plasmid treated animals. Hematological parameters were also significantly improved. Protein metabolism changes were observed suggesting a shift from a catabolic to an anabolic state in the treated animals. Blood urea nitrogen and creatinine did not show any significant changes suggesting maintenance of kidney function whereas the control animal's renal function deteriorated. Treated animals survived longer than control animals with 70% of dogs and 80% of cats surviving until study day 75. Only 17% and 40% of the control dogs and cats, respectively, survived to day 75. CONCLUSION: Improved quality of life, survival and general well-being indicate that further investigation is warranted, and show the potential of a plasmid-based therapy by electroporation in preventing and managing complications of renal insufficiency.

Double-blinded, Placebo-controlled plasmid GHRH trial for cancer-associated anemia in dogs.

The use of growth hormone releasing hormone (GHRH) plasmid-based therapy to treat companion dogs with spontaneous malignancies and anemia receiving a cancer-specific treatment was examined in a double-blinded, placebo-controlled trial. The dogs (age 10.5 +/- 2.5 years, weight 24.9 +/- 12.9 kg) received a single 0.35 mg dose of plasmid or placebo intramuscularly (i.m.), followed by electroporation (EP), and were analyzed for up to 120 days. The response rate was defined as > or = 5% increase above the nadir in the red blood cell (RBC), hemoglobin (Hb), and hematocrit (Ht) levels. Plasmid-treated dogs had at least a 7% increase in all three parameters. The initial response rates for the plasmid-treated dogs were 40.6 and 35.5%, respectively on days 40 and 60, which increased to 54.2% on day 90. Although the response rate reduced to 47.1% by day 120, it was still 22.1% higher than in the control dogs. Post-hoc analysis of the GHRH-treated group showed that responder dogs survived 84% longer, 178 +/- 26 days post-treatment, while nonresponders and controls survived for 95 +/- 16 and 97 +/- 31 days post-treatment, respectively. The quality of life, defined by 10 different parameters, dramatically improved with treatment. Overall, the possibility of a GHRH plasmid-based therapy for anemia in cancer-afflicted subjects is important enough to deserve further investigation.

Growth hormone-releasing hormone plasmid treatment by electroporation decreases offspring mortality over three pregnancies.

LifeTideSW5 is a growth hormone-releasing hormone (GHRH)-expressing plasmid delivered by intramuscular (IM) electroporation (EP), and the first therapeutic plasmid delivered by this physical method to be approved for use in food animals. Gestating sows (n = 997) were treated once with a single 5-mg GHRH-plasmid by EP or served as controls. Data on offspring from three parities subsequent to treatment were collected. No adverse effects related to treatment were noted. First parity post-treatment offspring from treated sows displayed a 2.93 kg (P < 0.0001) increase in carcass weight (CW), 1.0 mm (P < 0.0001) less back-fat (P2), and a 27.0 g CW/day (P < 0.0001) increase in rate of gain (ROG) compared with controls. An increase of 21.6% was recorded in the number of offspring surviving. In the second and third parities post-treatment, offspring from treated females displayed higher number of born alive and total born number, and lower stillborn rates. Third parity offspring from treated sows displayed a 1.6 kg advantage in CW (P < 0.05), 1.0 mm less P2 (P < 0.05), and a 10.0 g CW/day benefit in ROG. Furthermore, offspring from treated females had a 19.04% lower post-wean loss rate. Overall, plasmid GHRH administration decreased morbidity and mortality in treated females and their offspring over three consecutive pregnancies.

Plasmid growth hormone releasing hormone therapy in healthy and laminitis-afflicted horses-evaluation and pilot study.

BACKGROUND: In vivo electroporation dramatically improves the potency of plasmid-mediated therapies, including in large animal models. Laminitis and arthritis are common and debilitating diseases in the horse, as well as humans. METHODS: The effects of growth hormone releasing hormone (GHRH) on healthy horses and on horses with laminitis that were followed for 6 months after a single intramuscular injection and electroporation of 2.5 mg of an optimized myogenic GHRH-expressing plasmid were examined. RESULTS: In the first study on six healthy horses, we observed a significant increase in body mass by day 180 compared to baseline (P < 0.003), and an increase in erythrocyte production (hematocrit, red blood cells, hemoglobin, P = 0.03). IGF-I levels were increased by 7% by day 120 (P = 0.02). A pilot study was performed on two horses with chronic laminitis, a vascular condition often associated with arthritis, with two horses with similar clinical disease serving as non-treated controls. Treated horses experienced an increase in weight compared to control horses that received standard care (P = 0.007). By 6 months post-treatment, treated subjects were rated pasture sound. Physical and radiographic evaluation demonstrated significant improvement with reduced inflammation and decreased lameness. CONCLUSIONS: These results demonstrate that a plasmid therapy delivered by electroporation can potentially be used to treat chronic conditions in horses, and possibly other very large mammals. While further studies are needed, overall this proof-of-concept work presents encouraging data for studying gene therapeutic treatments for Raynaud's syndrome and arthritis in humans.