Development of Next-Generation COVID-19 Vaccines: Biomedical Advanced Research and Development Authority (BARDA-)-Supported Phase 2b Study Designs.

In response to the coronavirus disease 2019 (COVID-19) pandemic, vaccines were quickly and successfully developed and deployed, saving millions of lives globally. While first-generation vaccines are safe and effective in preventing disease caused by SARS-CoV-2, next-generation vaccines have the potential to improve efficacy and safety. Vaccines delivered by a mucosal route may elicit greater protective immunity at respiratory surfaces, thereby reducing transmission. Inclusion of viral antigens in addition to the spike protein may enhance protection against emerging variants of concern. Next-generation vaccine platforms with a new mechanism of action may necessitate efficacy trials to fulfill regulatory requirements. The Biomedical Advanced Research and Development Authority (BARDA) will be supporting Phase 2b clinical trials of candidate next-generation vaccines. The primary endpoint will be improved efficacy in terms of symptomatic disease relative to a currently approved COVID-19 vaccine. In this paper, we discuss the planned endpoints and potential challenges to this complex program.

Developing Vaccines to Improve Preparedness for Filovirus Outbreaks: The Perspective of the USA Biomedical Advanced Research and Development Authority (BARDA).

Outbreaks of viral hemorrhagic fever caused by filoviruses have become more prevalent in recent years, with outbreaks of Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV) all occurring in 2022 and 2023. While licensed vaccines are now available for EBOV, vaccine candidates for SUDV and MARV are all in preclinical or early clinical development phases. During the recent outbreak of SUDV virus disease, the Biomedical Advanced Research and Development Authority (BARDA), as part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, implemented key actions with our existing partners to advance preparedness and enable rapid response to the outbreak, while also aligning with global partners involved in the implementation of clinical trials in an outbreak setting. Beyond pre-existing plans prior to the outbreak, BARDA worked with product sponsors to expedite manufacturing of vaccine doses that could be utilized in clinical trials. While the SUDV outbreak has since ended, a new outbreak of MARV disease has emerged. It remains critical that we continue to advance a portfolio of vaccines against SUDV and MARV while also expediting manufacturing activities ahead of, or in parallel if needed, outbreaks.

IL-10 induction by Bordetella parapertussis limits a protective IFN-gamma response.

Bordetella parapertussis causes the prolonged coughing illness known as pertussis or whooping cough, persisting for weeks within the respiratory tracts of infected hosts but inducing a very poor T cell response relative to that induced by Bordetella pertussis, the more common cause of pertussis. In this study, we examine the contributions of cytokines involved in the clearance of B. parapertussis and immunomodulation that delays effective clearance. The slow elimination of this pathogen from the respiratory tracts of mice coincides with the gradual accumulation of CD4(+) T cells in the lungs and B. parapertussis-responsive IFN-gamma-producing cells in the spleen. IFN-gamma-deficient mice were defective in the accumulation of leukocytes in lungs and in clearance of B. parapertussis from the lungs. In vitro B. parapertussis-stimulated macrophages produced IL-10, which inhibited the generation of the IFN-gamma response that is required for protection in vivo. As compared with wild-type mice, IL-10-deficient mice produced significantly higher levels of IFN-gamma, had higher numbers of leukocytes accumulated in the lungs, and cleared B. parapertussis more rapidly. Together, these data indicate that B. parapertussis induces the production of IL-10, which facilitates its persistence within infected hosts by limiting a protective IFN-gamma response.

Utilization of Viral Vector Vaccines in Preparing for Future Pandemics.

As the global response to COVID-19 continues, government stakeholders and private partners must keep an eye on the future for the next emerging viral threat with pandemic potential. Many of the virus families considered to be among these threats currently cause sporadic outbreaks of unpredictable size and timing. This represents a major challenge in terms of both obtaining sufficient funding to develop vaccines, and the ability to evaluate clinical efficacy in the field. However, this also presents an opportunity in which vaccines, along with robust diagnostics and contact tracing, can be utilized to respond to outbreaks as they occur, and limit the potential for further spread of the disease in question. While mRNA-based vaccines have proven, during the COVID-19 response, to be an effective and safe solution in terms of providing a rapid response to vaccine development, virus vector-based vaccines represent a class of vaccines that can offer key advantages in certain performance characteristics with regard to viruses of pandemic potential. Here, we will discuss some of the key pros and cons of viral vector vaccines in the context of preparing for future pandemics.

Partnering on vaccines to counter multi-drug resistant threats: Workshop proceedings, Biomedical Advanced Research and Development Authority.

On March 12, 2021, the Biomedical Advanced Research and Development Authority (BARDA) sponsored a virtual market research workshop, "Partnering on Vaccines to Counter Multi-Drug Resistant Threats," to discuss the threat of antimicrobial resistance in the context of BARDA's mission space and the challenges encountered during the development of vaccines for specific antimicrobial resistant bacteria. The workshop convened representatives with expertise in vaccine development from government, academia, and industry. This report summarizes the presentations and subsequent discussions from the workshop and highlights existing challenges to advance the development of vaccine candidates for antimicrobial resistant pathogens, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus.

The Evolution of Medical Countermeasures for Ebola Virus Disease: Lessons Learned and Next Steps.

The Ebola virus disease outbreak that occurred in Western Africa from 2013-2016, and subsequent smaller but increasingly frequent outbreaks of Ebola virus disease in recent years, spurred an unprecedented effort to develop and deploy effective vaccines, therapeutics, and diagnostics. This effort led to the U.S. regulatory approval of a diagnostic test, two vaccines, and two therapeutics for Ebola virus disease indications. Moreover, the establishment of fieldable diagnostic tests improved the speed with which patients can be diagnosed and public health resources mobilized. The United States government has played and continues to play a key role in funding and coordinating these medical countermeasure efforts. Here, we describe the coordinated U.S. government response to develop medical countermeasures for Ebola virus disease and we identify lessons learned that may improve future efforts to develop and deploy effective countermeasures against other filoviruses, such as Sudan virus and Marburg virus.

Natural History of Sudan ebolavirus to Support Medical Countermeasure Development.

Sudan ebolavirus (SUDV) is one of four members of the Ebolavirus genus known to cause Ebola Virus Disease (EVD) in humans, which is characterized by hemorrhagic fever and a high case fatality rate. While licensed therapeutics and vaccines are available in limited number to treat infections of Zaire ebolavirus, there are currently no effective licensed vaccines or therapeutics for SUDV. A well-characterized animal model of this disease is needed for the further development and testing of vaccines and therapeutics. In this study, twelve cynomolgus macaques (Macaca fascicularis) were challenged intramuscularly with 1000 PFUs of SUDV and were followed under continuous telemetric surveillance. Clinical observations, body weights, temperature, viremia, hematology, clinical chemistry, and coagulation were analyzed at timepoints throughout the study. Death from SUDV disease occurred between five and ten days after challenge at the point that each animal met the criteria for euthanasia. All animals were observed to exhibit clinical signs and lesions similar to those observed in human cases which included: viremia, fever, dehydration, reduced physical activity, macular skin rash, systemic inflammation, coagulopathy, lymphoid depletion, renal tubular necrosis, hepatocellular degeneration and necrosis. The results from this study will facilitate the future preclinical development and evaluation of vaccines and therapeutics for SUDV.

Natural History of Marburg Virus Infection to Support Medical Countermeasure Development.

The Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, recognizes that the evaluation of medical countermeasures under the Animal Rule requires well-characterized and reproducible animal models that are likely to be predictive of clinical benefit. Marburg virus (MARV), one of two members of the genus Marburgvirus, is characterized by a hemorrhagic fever and a high case fatality rate for which there are no licensed vaccines or therapeutics available. This natural history study consisted of twelve cynomolgus macaques challenged with 1000 PFU of MARV Angola and observed for body weight, temperature, viremia, hematology, clinical chemistry, and coagulation at multiple time points. All animals succumbed to disease within 8 days and exhibited signs consistent with those observed in human cases, including viremia, fever, systemic inflammation, coagulopathy, and lymphocytolysis, among others. Additionally, this study determined the time from exposure to onset of disease manifestations and the time course, frequency, and magnitude of the manifestations. This study will be instrumental in the design and development of medical countermeasures to Marburg virus disease.

Immune correlates analysis of the ENSEMBLE single Ad26.COV2.S dose vaccine efficacy clinical trial.

Measuring immune correlates of disease acquisition and protection in the context of a clinical trial is a prerequisite for improved vaccine design. We analysed binding and neutralizing antibody measurements 4 weeks post vaccination as correlates of risk of moderate to severe-critical COVID-19 through 83 d post vaccination in the phase 3, double-blind placebo-controlled phase of ENSEMBLE, an international randomized efficacy trial of a single dose of Ad26.COV2.S. We also evaluated correlates of protection in the trial cohort. Of the three antibody immune markers we measured, we found most support for 50% inhibitory dilution (ID50) neutralizing antibody titre as a correlate of risk and of protection. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; P = 0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID50 (<2.7 IU50 ml-1) and increased to 89% (78%, 96%) at ID50 = 96.3 IU50 ml-1. Comparison of the vaccine efficacy by ID50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID50 titre as a correlate of protection across trials and vaccine types.

Immune Correlates Analysis of a Single Ad26.COV2.S Dose in the ENSEMBLE COVID-19 Vaccine Efficacy Clinical Trial.

Anti-spike IgG binding antibody, anti-receptor binding domain IgG antibody, and pseudovirus neutralizing antibody measurements four weeks post-vaccination were assessed as correlates of risk of moderate to severe-critical COVID-19 outcomes through 83 days post-vaccination and as correlates of protection following a single dose of Ad26.COV2.S COVID-19 vaccine in the placebo-controlled phase of ENSEMBLE, an international, randomized efficacy trial. Each marker had evidence as a correlate of risk and of protection, with strongest evidence for 50% inhibitory dilution (ID50) neutralizing antibody titer. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; p=0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43, 72%) at nonquantifiable ID50 (< 2.7 IU50/ml) and rose to 89% (78, 96%) at ID50 = 96.3 IU50/ml. Comparison of the vaccine efficacy by ID50 titer curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine, and the COV002-UK trial of the AZD1222 vaccine supported consistency of the ID50 titer correlate of protection across trials and vaccine types.

Selection of Filovirus Isolates for Vaccine Development Programs.

The continuing outbreaks of ebola virus disease highlight the ongoing threat posed by filoviruses. Fortunately, licensed vaccines and therapeutics are now available for Zaire ebolavirus. However, effective medical countermeasures, such as vaccines for other filoviruses such as Sudan ebolavirus and the Marburg virus, are presently in early stages of development and, in the absence of a large outbreak, would require regulatory approval via the U.S. Food and Drug Administration (FDA) Animal Rule. The selection of an appropriate animal model and virus challenge isolates for nonclinical studies are critical aspects of the development program. Here, we have focused on the recommendation of challenge isolates for Sudan ebolavirus and Marburg virus. Based on analyses led by the Filovirus Animal and Nonclinical Group (FANG) and considerations for strain selection under the FDA Guidance for the Animal Rule, we propose prototype virus isolates for use in nonclinical challenge studies.

Current State of Anthrax Vaccines and Key R&D Gaps Moving Forward.

A licensed anthrax vaccine has been available for pre-exposure prophylaxis in the United States since 1970, and it was approved for use as a post-exposure prophylaxis, in combination with antibiotic treatment, in 2015. A variety of other vaccines are available in other nations, approved under various regulatory frameworks. However, investments in anthrax vaccines continue due to the severity of the threat posed by this bacterium, as both a naturally occurring pathogen and the potential for use as a bioweapon. In this review, we will capture the current landscape of anthrax vaccine development, focusing on those lead candidates in clinical development. Although approved products are available, a robust pipeline of candidate vaccines are still in development to try to address some of the key research gaps in the anthrax vaccine field. We will then highlight some of the most pressing needs in terms of anthrax vaccine research.

Lessons learned from Zaire ebolavirus to help address urgent needs for vaccines against Sudan ebolavirus and Marburg virus.

The 2014-2016 Ebola virus epidemic in West Africa triggered extensive investments from public and private partners in an attempt to slow the spread of disease and bring the outbreak under control. This significantly accelerated the pace of development of countermeasures against Zaire ebolavirus that enabled vaccines to be a part of an effective response to the most recent 2018-2019 outbreak in the Democratic Republic of the Congo. However, there remain urgent and unmet needs for medical countermeasures against other members of the Filoviridae family that cause viral hemorrhagic fevers. To improve the national and global preparedness posture for viral hemorrhagic fevers, a renewed emphasis is being placed on developing vaccines for filoviruses other than Zaire ebolavirus. Here we discuss lessons learned from the West Africa epidemic and how those lessons apply to the development of vaccine candidates for other filoviruses, specifically Sudan ebolavirus and Marburg virus. This commentary will highlight some of the key product development gaps to address in preparation for future disease outbreaks caused by these viruses.

Evaluation of BioThrax® and AV7909 anthrax vaccines in adults 66 years of age or older.

BACKGROUND: Multiple Anthrax vaccines are licensed or in development for post-exposure prophylaxis in individuals 18 to 65 years of age. No information exists on anthrax vaccines in populations over the age of 65. It is critical that we assess the capacity of anthrax vaccines to generate a protective immune response in older individuals. In this study, we compared BioThrax® to a formulation containing a CpG adjuvant (AV7909). METHODS: We conducted a Phase 2 clinical study to evaluate safety and immunogenicity of three vaccination schedules of the AV7909 vaccine candidate and one vaccination schedule of BioThrax® vaccine in adults over 65 years of age. A total of 305 subjects were enrolled to assess safety and immunogenicity by seroprotection rates, toxin neutralizing antibody titers, and anti-Protective Antigen ELISA titers. RESULTS: Compared to BioThrax, AV7909 elicited a more robust immune response in older subjects, especially with three doses of AV7909 at Days 1, 15, and 29, or two doses at Days 1 and 29. These trends were true with both seroprotection rates as defined by the percentage of subjects with 50 percent neutralization factors greater than 0.56, and geometric mean antibody titers. The responses to both AV7909 and BioThax were lower in older subjects compared to those aged 18-50. CONCLUSION: The immunogenicity data suggest that the CpG adjuvant in the AV7909 vaccine helps to elicit a more robust immune response in subjects over the age of 65. Alternative dosing strategies may be considered in this population given the high seroprotection rates with Day 1 and 29, or Day 1, 15, and 29 regimens. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03518125.

Progress towards a vaccine against Ebola to meet emergency medical countermeasure needs.

The Ebola virus epidemic in West Africa proved to be the largest in the history of filovirus outbreaks, causing the World Health Organization to declare a public health emergency of international concern in August of 2014. In collaboration with domestic and international partners, the Biomedical Advanced Research and Development Authority (BARDA) initiated several vaccine development projects in support of the overall response efforts. The urgency associated with the epidemic triggered the clinical evaluation of lead vaccine candidates starting in late 2014. Here we will discuss development of the lead vaccine candidates for Ebola virus, specifically Zaire ebolavirus.

O antigen protects Bordetella parapertussis from complement.

Bordetella pertussis, a causative agent of whooping cough, expresses BrkA, which confers serum resistance, but the closely related human pathogen that also causes whooping cough, Bordetella parapertussis, does not. Interestingly, B. parapertussis, but not B. pertussis, produces an O antigen, a factor shown in other models to confer serum resistance. Using a murine model of infection, we determined that O antigen contributes to the ability of B. parapertussis to colonize the respiratory tract during the first week of infection, but not thereafter. Interestingly, an O antigen-deficient strain of B. parapertussis was not defective in colonizing mice lacking the complement cascade. O antigen prevented both complement component C3 deposition on the surface and complement-mediated killing of B. parapertussis. In addition, O antigen was required for B. parapertussis to systemically spread in complement-sufficient mice, but not complement-deficient mice. These data indicate that O antigen enables B. parapertussis to efficiently colonize the lower respiratory tract by protecting against complement-mediated control and clearance.

Different mechanisms of vaccine-induced and infection-induced immunity to Bordetella bronchiseptica.

A recent resurgence in the number of cases of whooping cough, and other respiratory diseases caused by members of the bordetellae, in vaccinated populations has demonstrated the need for a thorough understanding of vaccine-induced immunity to facilitate more intelligent vaccine design. In this work, we use a murine model of respiratory infection using the highly successful animal pathogen, Bordetella bronchiseptica. Since previously infected animals have been shown to resist re-infection by B. bronchiseptica, we sought to examine the differences between vaccine-induced immunity and infection-induced immunity. Both prior infection and vaccination conferred nearly complete protection in the lungs, however, only prior infection resulted in significant protection in the upper respiratory tract. While immunity induced by prior infection offered significant protection even in the absence of complement or FcgammaRs, vaccination-induced protection required both complement and FcgammaRs. Although vaccination induced higher titers of B. bronchiseptica-specific antibodies, this serum was less effective than infection-induced serum in clearing bacteria from the lower respiratory tract. Together these findings highlight substantial differences between the mechanisms involved in vaccine- and infection-induced protective immunity.

Vaccination against Q fever for biodefense and public health indications.

Coxiella burnetii is the etiological agent of Q fever, a disease that is often spread to humans via inhalational exposure to the bacteria from contaminated agricultural sources. Outbreaks have been observed all over the world with larger foci generating interest in vaccination programs, most notably in Australia and the Netherlands. Importantly, exposure rates among military personnel deployed to the Middle East can be relatively high as measured by seroconversion to C. burnetii-specific antibodies. Q fever has been of interest to the biodefense community over the years due to its low infectious dose and environmental stability. Recent advances in cell-free growth and genetics of C. burnetii also make this organism easier to culture and manipulate. While there is a vaccine that is licensed for use in Australia, the combination of biodefense- and public health-related issues associated with Q fever warrant the development of a safer and more effective vaccine against this disease.