Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens

Vaccines are one of the greatest public health achievements and have saved millions of lives. They represent a key countermeasure to limit epidemics caused by emerging infectious diseases. The Ebola virus disease crisis in West Africa dramatically revealed the need for a rapid and strategic development of vaccines to effectively control outbreaks. Seven years later, in light of the SARS-CoV-2 pandemic, this need has never been as urgent as it is today. Vaccine development and implementation of clinical trials have been greatly accelerated, but still lack strategic design and evaluation. Responses to vaccination can vary widely across individuals based on factors like age, microbiome, co-morbidities and sex. The latter aspect has received more and more attention in recent years and a growing body of data provide evidence that sex-specific effects may lead to different outcomes of vaccine safety and efficacy. As these differences might have a significant impact on the resulting optimal vaccine regimen, sex-based differences should already be considered and investigated in pre-clinical and clinical trials. In this Review, we will highlight the clinical observations of sex-specific differences in response to vaccination, delineate sex differences in immune mechanisms, and will discuss the possible resulting implications for development of vaccine candidates against emerging infections. As multiple vaccine candidates against COVID-19 that target the same antigen are tested, vaccine development may undergo a decisive change, since we now have the opportunity to better understand mechanisms that influence vaccine-induced reactogenicity and effectiveness of different vaccines.

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Protective population behavior change in outbreaks of emerging infectious disease

BMC Infectious Diseases ◽

10.1186/s12879-021-06299-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Evans K. Lodge ◽

Annakate M. Schatz ◽

John M. Drake

Keyword(s):

Behavior Change ◽

Ebola Virus ◽

Virus Disease ◽

Population Level ◽

Emerging Infections ◽

Emerging Pathogens ◽

Susceptible Population ◽

Zoonotic Infections ◽

Zoonotic Viruses ◽

And Behavior

Abstract Background During outbreaks of emerging and re-emerging infections, the lack of effective drugs and vaccines increases reliance on non-pharmacologic public health interventions and behavior change to limit human-to-human transmission. Interventions that increase the speed with which infected individuals remove themselves from the susceptible population are paramount, particularly isolation and hospitalization. Ebola virus disease (EVD), Severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS) are zoonotic viruses that have caused significant recent outbreaks with sustained human-to-human transmission. Methods This investigation quantified changing mean removal rates (MRR) and days from symptom onset to hospitalization (DSOH) of infected individuals from the population in seven different outbreaks of EVD, SARS, and MERS, to test for statistically significant differences in these metrics between outbreaks. Results We found that epidemic week and viral serial interval were correlated with the speed with which populations developed and maintained health behaviors in each outbreak. Conclusions These findings highlight intrinsic population-level changes in isolation rates in multiple epidemics of three zoonotic infections with established human-to-human transmission and significant morbidity and mortality. These data are particularly useful for disease modelers seeking to forecast the spread of emerging pathogens.

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Ebola: Lessons on Vaccine Development

Annual Review of Microbiology ◽

10.1146/annurev-micro-090817-062414 ◽

2018 ◽

Vol 72 (1) ◽

pp. 423-446 ◽

Cited By ~ 15

Author(s):

Heinz Feldmann ◽

Friederike Feldmann ◽

Andrea Marzi

Keyword(s):

Ebola Virus ◽

Vaccine Development ◽

Vaccine Safety ◽

West African ◽

Pharmaceutical Companies ◽

Effective Response ◽

Active Response ◽

Vaccine Candidates ◽

Limited Degree ◽

Competing Priorities

The West African Ebola virus (EBOV) epidemic has fast-tracked countermeasures for this rare, emerging zoonotic pathogen. Until 2013–2014, most EBOV vaccine candidates were stalled between the preclinical and clinical milestones on the path to licensure, because of funding problems, lack of interest from pharmaceutical companies, and competing priorities in public health. The unprecedented and devastating epidemic propelled vaccine candidates toward clinical trials that were initiated near the end of the active response to the outbreak. Those trials did not have a major impact on the epidemic but provided invaluable data on vaccine safety, immunogenicity, and, to a limited degree, even efficacy in humans. There are plenty of lessons to learn from these trials, some of which are addressed in this review. Better preparation is essential to executing an effective response to EBOV in the future; yet, the first indications of waning interest are already noticeable.

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Self-Replicating RNA Viruses for Vaccine Development Against Infectious Diseases and Cancer

10.20944/preprints202107.0261.v1 ◽

2021 ◽

Author(s):

Kenneth Lundstrom

Keyword(s):

Clinical Trials ◽

Infectious Diseases ◽

Immune Responses ◽

Measles Virus ◽

Viral Vectors ◽

Ebola Virus ◽

Vaccine Development ◽

Rna Viruses ◽

Vaccine Candidates ◽

Vector Systems

Alphaviruses, flaviviruses, measles viruses and rhabdoviruses are enveloped single-stranded RNA viruses, which have been engineered as expression vector systems for recombinant protein expression and vaccine development. Due to the presence of non-structural genes encoding the replicase complex, a 200,000-fold amplification of viral RNA occurs in the cytoplasm of infected cells providing extreme transgene expression levels, which is why they are named self-replicating RNA viruses. Expression of surface proteins of pathogens causing infectious disease and tumor antigens provide the basis for vaccine development against infectious diseases and cancer. The self-replicating RNA viral vectors can be administered as replicon RNA, recombinant viral particles, or layered DNA/RNA replicons. Self-replicating RNA viral vectors have been applied for vaccine development against influenza virus, HIV, hepatitis B virus, human papilloma virus, Ebola virus and recently coronaviruses, especially SARS-CoV-2 the causative agent of the COVID-19 pandemic. Measles virus and rhabdovirus vector-based SARS-CoV-2 vaccine candidates have been subjected to clinical trials. Moreover, RNA vaccine candidates based on self-amplifying alphaviruses have also been evaluated in clinical settings. Various cancers such as brain, breast, lung, ovarian, prostate cancer and melanoma have also been targeted for vaccine development. Robust immune responses and protection have been demonstrated in animal models. Clinical trials have shown good safety and target-specific immune responses. Ervebo, the VSV-based vaccine against Ebola virus disease has been approved for human use.

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Ebolavirus: Comparison of Survivor Immunology and Animal Models in the Search for a Correlate of Protection

Frontiers in Immunology ◽

10.3389/fimmu.2020.599568 ◽

2021 ◽

Vol 11 ◽

Author(s):

Stephanie Longet ◽

Jack Mellors ◽

Miles W. Carroll ◽

Tom Tipton

Keyword(s):

Clinical Trials ◽

Animal Models ◽

Immune Responses ◽

Ebola Virus ◽

Democratic Republic ◽

Vaccine Development ◽

Democratic Republic Of Congo ◽

Virus Disease ◽

Correlate Of Protection ◽

Host Immune Responses

Ebola viruses are enveloped, single-stranded RNA viruses belonging to the Filoviridae family and can cause Ebola virus disease (EVD), a serious haemorrhagic illness with up to 90% mortality. The disease was first detected in Zaire (currently the Democratic Republic of Congo) in 1976. Since its discovery, Ebola virus has caused sporadic outbreaks in Africa and was responsible for the largest 2013–2016 EVD epidemic in West Africa, which resulted in more than 28,600 cases and over 11,300 deaths. This epidemic strengthened international scientific efforts to contain the virus and develop therapeutics and vaccines. Immunology studies in animal models and survivors, as well as clinical trials have been crucial to understand Ebola virus pathogenesis and host immune responses, which has supported vaccine development. This review discusses the major findings that have emerged from animal models, studies in survivors and vaccine clinical trials and explains how these investigations have helped in the search for a correlate of protection.

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Accelerating R&D for Emerging Infectious Diseases: Lessons Learnt From Ebola

10.21203/rs.3.rs-38612/v1 ◽

2020 ◽

Author(s):

Chao Li ◽

Jingyi Chen ◽

Jiyan Ma ◽

Yangmu Huang

Keyword(s):

Clinical Trials ◽

Ebola Virus ◽

Virus Disease ◽

Emerging Infectious Diseases ◽

Basic Research ◽

Influential Factors ◽

Government Support ◽

Structured Interviews ◽

Clinical Trial Registries ◽

The U.S

Abstract Objective: The R&D explosion for Ebola virus disease (EVD) during the 2014-2016 outbreak led to the successful development of high-quality vaccines performed by China and the U.S. This study aims to compare the R&D activities of Ebola-related medical products in two countries, as a way to present the influential factors of R&D for emerging infectious disease (EID) and to provide suggestions for timely and efficient R&D response to the COVID-19 pandemic.Methods: In this comparative study, R&D activities were analyzed in terms of research funding, scientific research outputs, R&D timeline, and government incentive and coordinated mechanisms. Quantitative analysis was performed using data retrieved from national websites, clinical trial registries and databases.Qualitative semi-structured interviews were conducted to explore perspectives of fifteen key informants from EID field, especially of those involved in Ebola product development. Findings: The funding gap between China and the U.S. was significant before 2014 and narrowed after the Ebola outbreak. Both research teams started basic studies prior to the Ebola outbreak; however, the U.S. got FDA approval for clinical trials 5 months earlier than China. The underlying gap reveals the lack of participation and support by private sectors, the stagnant transformation platform, and the inadequate government incentives in China. Conclusion: R&D pre-planning and resource deployment mechanisms are crucial for EID preparedness and response. Funding should be allocated to support diversified R&D institutions for coping with the risks. Building private and public collaboration, and strengthening government support for clinical trials may accelerate the translation of basic research.

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Biological Hazards

10.1093/oso/9780190662677.003.0016 ◽

2017 ◽

Author(s):

Mark Russi

Keyword(s):

Ebola Virus ◽

Virus Disease ◽

Middle Eastern ◽

H1n1 Influenza ◽

Emerging Infections ◽

Bloodborne Pathogens ◽

Oral Transmission ◽

B Virus ◽

Animal Contact ◽

Novel H1n1 Influenza

This chapter describes various biological hazards and their impact on workers and others. A major focus of the chapter is biological hazards in healthcare and laboratory settings, including exposure to bloodborne pathogens and prevention of diseases related to them. Sections deal with sharps injuries, HIV/AIDS, hepatitis B virus, hepatitis C virus, tuberculosis, and other infectious diseases that can be acquired in the work environment via direct contact, droplet or airborne spread, or fecal-oral transmission. In addition, infectious agents spread by animal contact or arthropod vectors in a broad range of settings will be addressed. Newly emerging infectious or re-emerging infections, such as those due to H5N1 and novel H1N1 influenza, Middle Eastern respiratory syndrome (MERS), and Ebola Virus Disease (EVD) as well as agents associated with bioterrorism are discussed.

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Self-Replicating RNA Viruses for RNA Therapeutics

Molecules ◽

10.3390/molecules23123310 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3310 ◽

Cited By ~ 13

Author(s):

Kenneth Lundstrom

Keyword(s):

Clinical Trials ◽

Phase I ◽

Tumor Cells ◽

Neutralizing Antibodies ◽

Ebola Virus ◽

Vaccine Development ◽

Rna Viruses ◽

Antibody Responses ◽

Phase Iii ◽

Phase I Clinical Trials

Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.

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Progress and challenges in TB vaccine development

F1000Research ◽

10.12688/f1000research.13588.1 ◽

2018 ◽

Vol 7 ◽

pp. 199 ◽

Cited By ~ 51

Author(s):

Gerald Voss ◽

Danilo Casimiro ◽

Olivier Neyrolles ◽

Ann Williams ◽

Stefan H.E. Kaufmann ◽

...

Keyword(s):

Clinical Trials ◽

Vaccine Development ◽

Scientific Progress ◽

Human Infection ◽

Experimental Medicine ◽

Vaccine Platform ◽

Vaccine Candidates ◽

Clinical Endpoints ◽

Immune Correlates ◽

Efficacy Trials

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development. To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models. However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

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Accelerating Vaccine Development During the 2013–2016 West African Ebola Virus Disease Outbreak

Current Topics in Microbiology and Immunology - Marburg- and Ebolaviruses ◽

10.1007/82_2017_53 ◽

2017 ◽

pp. 229-261 ◽

Cited By ~ 1

Author(s):

Elizabeth S. Higgs ◽

Sheri A. Dubey ◽

Beth A. G. Coller ◽

Jakub K. Simon ◽

Laura Bollinger ◽

...

Keyword(s):

Ebola Virus ◽

Vaccine Development ◽

Virus Disease ◽

Disease Outbreak ◽

West African ◽

Ebola Virus Disease

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Impacts of environmental and socio-economic factors on emergence and epidemic potential of Ebola in Africa

Nature Communications ◽

10.1038/s41467-019-12499-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 10

Author(s):

David W. Redding ◽

Peter M. Atkinson ◽

Andrew A. Cunningham ◽

Gianni Lo Iacono ◽

Lina M. Moses ◽

...

Keyword(s):

Ebola Virus ◽

Virus Disease ◽

Emerging Infectious Diseases ◽

Central Africa ◽

Fold Increase ◽

Healthcare Intervention ◽

Economic Factors ◽

Modelling Framework ◽

Global Change Scenarios ◽

Socio Economic Factors

Abstract Recent outbreaks of animal-borne emerging infectious diseases have likely been precipitated by a complex interplay of changing ecological, epidemiological and socio-economic factors. Here, we develop modelling methods that capture elements of each of these factors, to predict the risk of Ebola virus disease (EVD) across time and space. Our modelling results match previously-observed outbreak patterns with high accuracy, and suggest further outbreaks could occur across most of West and Central Africa. Trends in the underlying drivers of EVD risk suggest a 1.75 to 3.2-fold increase in the endemic rate of animal-human viral spill-overs in Africa by 2070, given current modes of healthcare intervention. Future global change scenarios with higher human population growth and lower rates of socio-economic development yield a 1.63-fold higher likelihood of epidemics occurring as a result of spill-over events. Our modelling framework can be used to target interventions designed to reduce epidemic risk for many zoonotic diseases.

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