Credit: CDC/Dr. Brodsky

NIAID STRATEGIC PLAN 

FOR RESEARCH TO 

DEVELOP A VALLEY 

FEVER VACCINE 

NIAID Valley Fever 

Research Working 

Group

September 2022
1 

Contents 

Executive Summary........................................................................................................................ 2

Introduction.................................................................................................................................... 4

Strategic Priority 1: Address Gaps in Coccidioides Basic Research to Support the Development 

of a Vaccine .................................................................................................................................... 6

Objective 1.1 Evaluate Factors Contributing to Coccidioides Geographic Spread...................... 6

Objective 1.2 Improve Understanding of Coccidioides Biology and Life Cycle........................... 7

Objective 1.3 Characterize Host Responses to Infection and Disease........................................ 7

Objective 1.4 Characterize Virulence Factors............................................................................. 8

Strategic Priority 2: Develop Tools and Resources to Support Coccidioides Vaccine Research.. 9

Objective 2.1: Advance Development of Biomarkers and Rapid Point-of-care Diagnostics.... 10

Objective 2.2: Develop Cell Culture and Animal Models that Reflect Human Disease ............ 11

Objective 2.3: Leverage and Expand Clinical Capacity to Promote Collaboration ................... 11

Strategic Priority 3: Develop and Advance Vaccines to Prevent Coccidioidomycosis............... 12

Objective 3.1: Support and Advance Rational Design of Vaccines for Valley fever.................. 12

Objective 3.2: Test Vaccine Candidates in Diverse Populations............................................... 13

Conclusion .................................................................................................................................... 13

Appendix 1. Valley Fever Strategic Plan Working Group Members........................................... 15

Appendix 2. Analysis of Public Comments to Request for Information (RFI)............................ 16

Appendix 3. Vaccine Development Benchmarks, Criteria, and Market Analysis for a Valley 

Fever Vaccine................................................................................................................................ 18

Appendix 4: NIAID-Supported Valley fever Research Resources............................................... 20
2 

Executive Summary 

The National Institute of Allergy and Infectious Diseases (NIAID) at the U.S. National Institutes 

of Health (NIH) is committed to advancing research on Valley fever, including the development 

of a safe and effective Valley fever vaccine. Valley fever—caused by the Coccidioides fungus—is 

one of the most common endemic fungal infections in the United States, with over 20,003

cases reported in 2019. The Coccidioides fungus resides in the soil and its spores can be inhaled

by people when the ground is disturbed, resulting in respiratory infection. Symptoms often 

resolve within a few months, but in some cases the Coccidioides fungus can cause severe 

pneumonia or disseminate to parts of the body beyond the lungs. Severe cases are more 

common in people who are immunocompromised, pregnant, 60 years of age and older, or 

members of certain racial and ethnic groups including Black and African Americans, and Asian 

Americans. 

Although Valley fever cases have been traditionally found in the arid regions of the 

southwestern United States and South America, the discovery of local spread in the Pacific 

Northwest suggests that changes in weather and climate may be increasing the geographic 

spread and incidence of Coccidioides infection. To date, Valley fever treatment strategies using 

antifungal drugs remain challenging because of the variability in disease severity and potential 

host risk factors, both of which impact the type and duration of treatment. More research is 

needed to identify better treatments for Valley fever. The increasing threat that Valley fever 

poses to public health underscores the urgent need for the development of safe and effective 

medical countermeasures 

Currently, no vaccine is licensed to 

prevent Valley fever, despite ongoing 

research since the 1960s. Because 

Coccidioides infection in people usually 

provides protective immunity from 

reinfection, developing a safe and 

effective vaccine is generally thought to be feasible and would be expected to provide durable 

immunity. A safe and effective vaccine against Coccidioides infection could protect residents in

the affected areas in the United States and other countries. 

To protect people against Coccidioides infection, the NIAID Strategic Plan for Research to 

Develop a Valley Fever Vaccine reflects the NIAID research priorities for developing a Valley 

fever vaccine. The plan outlines three strategic priorities to achieve this goal: 

• Strategic Priority 1: Address Gaps in Coccidioides Basic Research to Support the 

Development of a Vaccine — elucidate epidemiological factors, geographical spread,

NIAID Strategic Plan for Research to Develop 

a Valley fever Vaccine

Mission: Develop a vaccine for Valley fever

Vision: Stop the increasing public health threat 

due to Valley fever 
3 

and fungal and host factors underlying pathogenesis and host immune response, 

including correlates of immunity

• Strategic Priority 2: Develop Tools and Resources to Support Coccidioides Vaccine 

Research— biomarkers, cell culture and animal models, diagnostics, and clinical 

research capacity

• Strategic Priority 3: Develop and Advance Vaccines to Prevent Coccidioidomycosis—

focus on strategies to advance vaccine design, adjuvants, and alternative delivery 

methods, prioritizing the inclusion of high-risk populations in clinical trial testing

These interdependent activities (Figure 1) will require a concerted effort by the research 

community and public health stakeholders to develop a safe and effective vaccine for Valley 

fever for use in at-risk populations. NIAID anticipates that this plan will serve as a basis for such 

activities as well as future research needed to develop a vaccine for Valley fever. 

Figure 1: NIAID Strategic Plan to develop a vaccine for Valley fever research priorities. Priority 1: Address gaps 

in Coccidioides basic research to support the development of a vaccine. Priority 2: Develop tools and resources to 

support Coccidioides vaccine research. Priority 3: Develop and advance vaccines to prevent coccidioidomycosis.
4 

Introduction 

Coccidioidomycosis, more commonly known as Valley fever, is a fungal infection of increasing 

public health concern in the U.S. Valley fever is most common in the arid regions of the 

southwestern U.S. and Central and South America and is among the most common endemic 

mycoses in the United States. Valley fever is caused by the soil-dwelling fungi Coccidioides 

immitis or Coccidioides posadasii that establish infection in the lung after inhalation. Although 

many cases of Valley fever are asymptomatic and self-limiting, approximately 40 percent of 

infected individuals develop significant flu-like symptoms including cough, fever, chest pain, 

and fatigue, which can last weeks to months and require antifungal therapy. In some cases, 

infection can spread to the brain, skin, or bones. Severe disease occurs in approximately one 

percent of infected individuals, resulting in severe morbidity or death and necessitating lifelong antifungal therapy. Approximately 200 coccidioidomycosis-associated deaths were

reported each year on average in the United States from 1999 to 2019. While disseminated

spread is rare, it is more common among certain racial and ethnic groups including Black and 

African Americans, Filipinos, people with a weakened immune system, and women during the 

third trimester of pregnancy. Additionally, rates of Valley fever are usually highest among 

people aged 60 and older. 

Although much progress has been made in understanding the biology of Coccidioides as well as 

the host response to infection, there are still significant gaps in scientific knowledge, molecular 

tools, and resources that need to be addressed. One of the challenges in research towards the 

development of a vaccine is the unique dimorphic life cycle of C. immitis and C. posadasii, which 

alternates between a saprobic, or soil-dwelling phase, and a spherule/endospore parasitic 

phase in an animal host (Figure 2). Transition between the saprobic phase and parasitic phases 

occurs when soil containing Coccidioides is disturbed and arthroconidia, or spores, are 

dispersed. In some cases, arthroconidia return to the ground and re-establish a saprobic lifecycle phase. In other cases, inhalation of arthroconidia by humans or animals supports the 

transition of the fungus into the parasitic phase. Inhaled arthroconidia undergo cellular changes 

and numerous rounds of nuclear division in the lungs, leading to the development of larger 

spherules and the production of numerous endospores, which result in sustained pathology in 

the host. 
5 

Figure 2: Coccidioides life cycle. Coccidioides have a unique dimorphic life cycle, which alternates between a saprobic (soildwelling) phase, and a spherule/endospore parasitic phase in an animal host. Transition between the saprobic phase and 

parasitic phase occurs when soil containing Coccidioides is disturbed and arthroconidia, or spores, are dispersed. In some cases, 

arthroconidia return to the ground and re-establish a saprobic life-cycle phase. In other cases, inhalation of arthroconidia by 

humans or animals supports the transition of the fungus into a parasitic phase. Inhaled arthroconidia undergo cellular changes 

and numerous rounds of nuclear division in the lungs leading to the development of larger spherules and the production of 

numerous endospores, which can result in disease. 

In 2019, the Centers for Disease Control and Prevention (CDC) reported 20,003 cases of Valley 

fever. However, many patients go undiagnosed or misdiagnosed due to delays in testing, 

suggesting that this may be an underestimate of cases. Historical trends suggest that the 

prevalence and geographic spread of Valley fever has steadily increased over the past decade, 

underscoring the urgency and need for the development of better medical countermeasures.

To address these issues and develop the NIAID Strategic Plan to Develop a Valley Fever Vaccine, 

a Valley Fever Working Group consisting of scientific, policy and subject matter experts within 

NIAID was convened to advance progress in the field where obstacles and significant gaps in 

scientific knowledge still exist. To seek broad public input, NIAID published a Valley fever 

Request for Information (RFI), and also targeted community stakeholders, such as

Southwestern Native communities. The RFI garnered responses from a variety of organizations

which were incorporated into this plan. Leveraging this broad expertise, this plan is organized 

around three interdependent strategic priorities to advance research towards the development 

of a Valley fever vaccine: understand Coccidioides pathogenesis and host responses, develop 
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tools and resources to support Coccidioides vaccine research, and develop and advance 

vaccines to prevent Coccidiomycosis. 

Strategic Priority 1: Address Gaps in Coccidioides Basic 

Research to Support the Development of a Vaccine

Developing a vaccine for Valley fever will require continued advances in the understanding of 

the complex molecular and immune mechanisms underlying infection and disease. Improving 

our understanding of the coccidioides life cycle and geographical spread is essential to 

understanding transmission and infection and informing the development of countermeasures. 

Strategic Priority 1: Address Gaps in Coccidioides Basic Research to 

Support the Development of a Vaccine

1. Evaluate Factors Contributing to Coccidioides Geographic Spread

2. Improve Understanding of Coccidioides Biology and Life Cycle

3. Characterize Host Responses to Infection and Disease

4. Characterize Virulence Factors

Objective 1.1 Evaluate Factors Contributing to Coccidioides Geographic Spread

Although most cases of coccidioidomycosis in the United States are seen in Arizona and 

California, the disease is also found in many arid and semi-arid regions throughout both 

American continents and cases have been identified in most states in the United States due to 

travel to endemic areas. Increases in the number of coccidioidomycosis cases have been 

associated with increasingly hot and dry weather conditions, suggesting that climate and 

changes in weather may also affect the geographic range and incidence of Coccidioides

infection. Locally acquired cases have been detected outside of the traditional endemic regions, 

including in Eastern Washington, Oregon, and Northern California. Further research is needed 

to understand the factors that contribute to Coccidioides prevalence and spread in the 

environment. 

The uneven distribution of Coccidioides in soil, including in areas undergoing outbreaks 

indicates that factors such as temperature, moisture, and soil composition may affect fungal

persistence and survival in the environment. Animal reservoirs have not been definitively 

determined. Small mammals, including rodents, may be reservoirs of Coccidioides that help 

facilitate spread to new geographic areas. NIAID is supporting research to correlate 

environmental changes and pathogen prevalence with the risk of Coccidioides infection. A more 

comprehensive evaluation of environmental factors and natural reservoirs contributing to 
7 

Coccidioides persistence and spread will better define areas of endemicity and identify 

populations at risk for Valley fever. 

In addition to environmental factors, fungal-specific factors may also contribute to 

dissemination. These changes may be elucidated through more comprehensive genomic 

evaluations and comparisons of the two Coccidioides species. These studies may provide 

insights into the organism's survival strategies within different ecological niches and enhance 

our understanding of disease spread. 

Objective 1.2 Improve Understanding of Coccidioides Biology and Life Cycle

Coccidioides are dimorphic fungi, exhibiting alternate morphological forms in the soil and 

animal host (Figure 2). In the soil, the fungus forms arthroconidia (or spores) that can become 

airborne. Once inhaled by a mammalian host, the arthroconidia transition to a parasitic phase, 

dividing and enlarging into spherules. The mature spherule eventually ruptures and releases 

numerous endospores. These endospores can spread to any organ system and in rare instances 

establish disseminated disease in the host that may require life-long antifungal therapy. 

This unique dimorphism presents challenges for immune detection and activation. There is a 

functional understanding of very few genes in Coccidioides spp. Genetic studies to increase 

understanding of Coccidioides biology during infection will help identify virulence factors, 

phenotypic variation, essential metabolic pathways, and immunogenic antigens that may be 

exploited as targets for vaccine development. To sustain this discovery research, NIAID will 

continue to prioritize the advancement of genetic tools and molecular resources to delineate 

Coccidioides biology and life cycle. 

Objective 1.3 Characterize Host Responses to Infection and Disease

While most healthy individuals infected with Coccidioides spp. experience an uncomplicated 

recovery and life-long immunity, individuals with suppressed or compromised immune systems

are at higher risk for disseminated disease and severe clinical outcomes which indicate that the 

host immune response plays a critical role in disease progression. Given that individuals who 

have been infected are mostly resistant to re-infection, it is likely that immune responses to 

Coccidioides can confer lasting immunity from disease. The specific mechanisms of this longterm protection and the molecular and cellular immune events leading to severe disease are 

not well understood.

Previous studies on Valley fever suggest that both innate and adaptive immunity may be

essential for the control of Coccidioides, but it remains unclear how these two arms of the 

immune system coordinate to clear the infection and establish durable immunity. Studies in 

animal models demonstrate that the innate immune response is important for recognition and
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control of Coccidioides infection, with specific C-type lectin-like receptors and Toll-like receptors

playing an essential role in the protection against infection and dissemination, respectively. 

While neutrophils and macrophages are known to be involved, the role of other innate immune 

cell types such as natural killer cells, dendritic cells, and eosinophils are poorly understood. 

Studies have also indicated that T-cells, particularly Th1 and Th17 responses contribute to 

adaptive immunity against Valley fever, but a better understanding of the cross-talk between 

the innate and adaptive immune responses required to produce lasting immunity to 

Coccidioides is needed.

Granuloma formation is a hallmark of Valley fever, yet the cellular ingredients required for the 

formation and maintenance of these complex structure is poorly characterized. It is unclear 

what cell types and signaling pathways are involved and little information is available about the 

immune microenvironment within the granuloma. Understanding the cellular communication

pathways associated with granulomas during different disease states may yield clues to identify 

protective and permissive host responses to Coccidioides. 

Additionally, individuals with certain genetic ancestries, such as Native Americans, Black and 

African Americans, Latinos, and Filipinos are at increased risk of developing disseminated 

disease, suggesting that genetic variants may impact host control of the pathogen and 

contribute to severe disease. However, the complex molecular pathways linking genetic 

ancestry and a dysregulated immune response leading to disease rather than dormant infection 

are poorly understood. Studies are needed to characterize genetic and other factors associated 

with protective or adverse clinical outcomes in populations at higher risk for disease. For 

example, large-scale, longitudinal cohorts would be useful for the detection of alleles 

associated with genetic risk. Machine learning may also aid in uncovering the genetic links to 

severe disease outcomes at the individual level. 

To meet this objective, NIAID is prioritizing research that will provide a basic foundation for an

understanding of the innate and adaptive immune response to Coccidioides. This effort will 

include characterizing the immunological compartments that coordinate and maintain 

immunity and describing human genetic and immunological risk factors that contribute to 

disease. The identification of host immune mechanisms and correlates associated with 

protection from disease after infection, or the progression to mild or severe disease will be

crucial to guiding the development of a safe and effective vaccine for Valley fever.

Objective 1.4 Characterize Virulence Factors

Although many cases of Valley fever are asymptomatic and self-limiting, approximately 40

percent of infected individuals develop significant flu-like symptoms in the weeks following 

inhalational exposure. In some cases, individuals experience spread of disease throughout the 
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body including to the brain, skin, or bones. The factors that drive pathogenesis in one particular 

organ system within an individual host are unknown. 

Identifying virulence factors that aid Coccidioides survival and immune evasion in the host has 

been hampered by the lack of genetic tools to manipulate gene expression and observe 

phenotypic changes. The unique dimorphic nature of Coccidioides also adds complexity to 

characterizing basic virulence factors. Currently, only a handful of virulence factors have been 

identified. The most thoroughly described are the spherule outer wall SOWgp and Mep1 that 

digests SOWgp to aid immune evasion during endosporulation. Additionally, a urease and a 

master transcription factor controlling expression of pathways essential for pathogenesis have 

been linked to virulence in the mammalian host. Given the dearth of identified Coccidioides

virulence factors, further studies are needed to elucidate the fungus-specific mechanisms that 

contribute to modulating pathogenesis, evading host detection, promoting dissemination, and 

enhancing disease severity. NIAID will continue to support research on virulence mechanisms 

associated with Coccidioides infection to expand our knowledge on Coccidioides pathogenesis 

and to identify targets that can be exploited for vaccine development. 

Strategic Priority 2: Develop Tools and Resources to Support 

Coccidioides Vaccine Research

Biomarkers, assays, and animal models are essential tools and resources for testing new 

vaccines and advancing Valley fever clinical studies. The identification of fungal and host 

biomarkers also support clinical trials by potentially serving as surrogate endpoints to help 

predict whether a vaccine is likely to have a desired effect in early-stage trials of candidate 

vaccines. Multi-disciplinary collaborations will also be needed to promote sharing of resources, 

tools, data, and samples for basic research, product testing, and clinical evaluation of promising 

vaccine candidates. 

Strategic Priority 2: Develop Tools and Resources to Support Coccidioides

Vaccine Research

1. Advance Development of Biomarkers and Rapid Point-of-care Diagnostics 

2. Develop Cell Culture and Animal Models that Reflect Human Disease 

3. Leverage and Expand Clinical Capacity to Promote Collaboration
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Objective 2.1: Advance Development of Biomarkers and Rapid Point-of-care 

Diagnostics 

Early symptoms of Valley fever are often difficult to distinguish from other pulmonary 

infections. Rapid and reliable point-of-care diagnostics that distinguish among uninfected 

individuals, people with active infection, and those with previously established immunity will be 

required for successful clinical development and testing of candidate vaccines. To prevent 

diagnosis delays, the assays should also be rapid and deployable in primary health care settings 

without a requirement for special equipment or personnel. NIAID will continue to support novel 

approaches to develop rapid point-of-care diagnostic tests for Valley fever. To address the need 

for new and improved diagnostics, significant efforts will be required to identify biomarkers 

that can be integrated into diagnostic platforms to provide accurate, reliable, and actionable 

information to clinicians. Reliable and convenient diagnostics also will improve patient care 

while vaccine development is underway.

New molecular diagnostics are needed for the direct detection of the pathogen. Conventional 

methods for diagnosing Valley fever rely primarily on culture methods, histopathology, and a 

variety of serologic assays that detect Coccidioides-specific IgG and IgM antibodies. While these 

serologic tests are clinically useful, they have limitations. By looking for antibodies as a marker 

of infection, serological tests do not detect the presence of a pathogen directly. Therefore they 

may miss an early infection when antibodies have not yet been produced. Conversely, in certain 

clinical contexts such as immunocompromised hosts, antibody titers may not reflect disease 

stage, severity, or clinical response to therapy.

As highlighted in Figure 2, Coccidioides has a complicated lifecycle within the human body and

may cause a heterogeneous clinical spectrum. Primary disease mostly affects the lungs and is

initiated by direct inhalation of arthroconidia. Secondary disease also affects the lungs and can 

become a chronic process. Disseminated disease (usually resulting from spread of a primary 

lung infection) can involve many organs including the skin, bones, joints, nervous system and 

meninges. The ability to detect the fungus accurately in this wide variety of tissues is 

challenging and may require different diagnostic approaches. In order to systematically test 

vaccine candidates the ability to accurately and uniformly diagnose individuals is paramount 

regardless of the stage of disease or the tissue affected. 

In addition to serving as the basis for clinical diagnosis and prognosis, identifying fungal and 

host biomarkers will be essential to facilitate clinical trials and may serve as surrogate 

endpoints in early stage trials of candidate vaccines. Surrogate endpoints may predict whether 

a vaccine is likely to have the desired protective effect and advance to later stage clinical 

testing. It is preferable that biomarker signatures come from easily obtainable samples such as 

peripheral blood, urine, stool, or volatiles, such as compounds that may be measured in the 
11

breath. NIAID will continue to support the identification and validation of host biomarkers to 

distinguish disease stages and response to interventions.

Objective 2.2: Develop Cell Culture and Animal Models that Reflect Human 

Disease 

The diverse pathology of Valley fever in humans combined with the biosafety level 3 (BSL3) 

containment conditions required for laboratory experiments in Coccidioides presents challenges

in the development of robust cell culture and animal models of disease that recapitulate human 

infection. Currently, mice are the primary animal model used in Coccidioides research and 

preclinical studies. However, Coccidioides infections have been shown to progress more rapidly 

in mice compared to humans, although advances have been made using genetically altered

mouse strains and attenuated Coccidioides to recapitulate human disease. Rabbit models have 

been developed, but given BSL3 requirements, rabbits are more costly and more difficult to 

manage. Naturally infected dogs and nonhuman primates (NHPs) in facilities located in endemic 

regions present opportunities to follow the diverse disease states but these types of 

approaches may lack statistical rigor. 

Additional animal models are needed that recapitulate both pulmonary and disseminated

disease states in humans. Mice are a very well-established model for Valley fever, but present 

some limitations since Coccidioides infection progresses rapidly in mice and the 

pharmacokinetics of drugs may differ significantly from humans. Other small animal models 

could be developed that more closely mimic human disease. Additionally, there could be 

opportunities to study and treat naturally infected dogs or NHPs in primate centers within the 

endemic area. Developing cutting edge in vitro models including organoids and mixed primary 

cultures that recapitulate the lung epithelium will serve as valuable, cost-effective

complements to animal models. NIAID will continue to support small and large animal models 

of Coccidioides and novel cell and tissue culture techniques to deepen the understanding of the 

host-pathogen interaction. 

Objective 2.3: Leverage and Expand Clinical Capacity to Promote Collaboration

Advancing Valley fever research toward the development of a vaccine will require leveraging 

and expanding clinical research capacity to promote collaboration. Multidisciplinary 

collaborations foster resource-sharing across disciplines which may result in better approaches 

for identifying clinical research sites and recruiting relevant diverse populations. It would also 

foster training and development of innovative Valley fever researchers. To support this 

objective, NIAID has established a network of Coccidioidomycosis Collaborative Research
12

Centers. These multi-disciplinary research teams conduct both clinical and basic research and 

will collaborate to investigate potential diagnostics, therapeutics, and vaccines for Valley fever. 

NIAID also funds multiple networks that can design and implement clinical trials for testing 

candidate vaccines and has clinical trial units dedicated to supporting vaccine research

(Appendix 4). NIAID will continue to build on its existing tools, resources, and investments in 

clinical research infrastructure and resources where Valley fever is endemic in the United 

States.

 

Strategic Priority 3: Develop and Advance Vaccines to Prevent 

Coccidioidomycosis 

Developing a vaccine to prevent coccidioidomycosis will require building on insights gained into 

the biology of Coccidioides and the immune mechanisms preventing or limiting disease. Ideal 

vaccine candidates should adhere to specific criteria (appendix 1) including being safe and 

effective in all populations, particularly individuals who are immunocompromised and at highest 

risk for disease. 

Strategic Priority 3: Develop and Advance Vaccines to Prevent 

Coccidioidomycosis

1. Support and Advance Rational Design of Vaccines for Valley fever

2. Test Vaccine Candidates in Diverse Populations

Objective 3.1: Support and Advance Rational Design of Vaccines for Valley fever

No fungal vaccines are currently approved for human use in the United States by the Food and 

Drug Administration (FDA). Nonetheless, the development of a prophylactic vaccine against 

coccidioidomycosis should be feasible because patients who recover from infection can acquire 

long-term immunity. Because of this, there is a long history of research on coccidioidomycosis 

vaccines. Early promising efforts included immunizing mice and NHPs with formalin-killed 

spherules. However, clinical trials using this strategy were stopped after the killed spherule 

vaccine did not demonstrate significant reduction of incidence or severity of disease and 

because of observed safety signals. Since then, advanced live-attenuated vaccine strategies 

have been evaluated that demonstrated efficacy in mice and dogs. Live-attenuated vaccine 

platforms will require rigorous testing to ensure safety, especially in immunocompromised 

individuals who typically are at risk for severe Valley fever. 

Recombinant subunit protein-based vaccine candidates offer an alternative to live-attenuated 

vaccine candidates. Many surface antigens of the spherule have been evaluated as potential 
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vaccine targets. In previous studies in animal models, vaccines using a single antigen provided

modest to moderate protection, suggesting multivalent vaccines may be needed for this 

approach. In this regard, an NIAID-supported recombinant protein approach used a multivalent 

polypeptide antigen comprised of three Coccidioides protein fragments and five human T-cell 

epitopes, and Glucan Chitin Particle (GCP) adjuvant. This vaccine candidate was shown to elicit 

a protective Th1/Th17 mediated immune response in mice, and the adjuvant requires further 

development before first in human studies can be initiated. 

To develop a safe and effective vaccine for the diverse populations at risk for Valley fever, 

including individuals who are immunocompromised, multiple vaccine approaches guided by 

rational vaccine design will be needed. Research into adjuvants will be crucial to enhance 

vaccine effectiveness. In particular, adjuvants that promote and sustain durable Th1/TH17 

immunity will be important. To support this effort, the NIAID Adjuvant Discovery Program, the 

NIAID Adjuvant Development Program, and NIAID Preclinical Services could be leveraged to 

advance novel adjuvants, improve the breadth and durability of novel immunogens, and 

evaluate vaccine delivery platforms. 

Objective 3.2: Test Vaccine Candidates in Diverse Populations

An ideal Valley fever vaccine for humans would need to be safe and effective in all populations, 

especially immunocompromised people, who are at highest risk of disease. Although previous 

studies in mice and dogs have highlighted the promise of a live-attenuated vaccine against 

Coccidioides, additional vaccine strategies will be necessary to achieve protection in more 

vulnerable populations for whom a live-attenuated vaccine may not be appropriate. Certain 

additional co-infections will need to be considered depending on geographic origin. For 

example, co-infections with tuberculosis and other regional mycoses, such as histoplasmosis, 

are prevalent in Latin and South America, and could affect responses to a Valley fever vaccine. 

Vaccine trial participants will need to reflect the diversity of the populations at risk of infection 

and the particular susceptibilities to disease. Additionally, prior studies have shown that a 

significant number of people in endemic regions possess some amount of immunity to 

Coccidioides from prior infections. The immune status of these individuals will need to be 

considered when conducting eligibility screening for enrollment into a Valley fever vaccine trial. 

Conclusion

The NIAID Strategic Plan for Research to Develop a Valley Fever Vaccine establishes scientific 

research priorities that will inform the development of a vaccine to address this growing public 

health need. This effort will require a continued commitment to advancing basic research on 

the biology of the pathogen and the immune response to it, the development and sharing of 

tools and resources to support the scientific community, and the development and testing of 
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promising vaccine candidates. These scientific priorities build on the framework of previous 

successful vaccine development efforts. To support these efforts, NIAID will also continue to

work with public health stakeholders and support collaborations to promote Valley fever 

research. 
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Appendix 1. Valley Fever Strategic Plan Working Group 

Members

Last Name First Name Position

Azeez Olumayowa Health Science Policy Analyst, Policy, Planning and Evaluation 

Branch, OD, NIAID

Bushar Nicholas Chief, Policy, Planning and Reporting Section, Policy, Planning 

and Evaluation Branch, OD, NIAID

Dixon Dennis Chief Bacteriology and Mycology Branch, Division of 

Microbiology and Infectious Diseases, NIAID

Ford Andrew Program Analyst, Office of Scientific Coordination and Program 

Operations, Division of Microbiology and Infectious Diseases, 

NIAID

Love Dona Mycology Program Officer, Division of Microbiology and 

Infectious Diseases, NIAID

Miers Sarah Program Analyst, Office of Scientific Coordination and Program 

Operations, Division of Microbiology and Infectious Diseases, 

NIAID

Perdue Sam Microbiologist, Division of Microbiology and Infectious 

Diseases, NIAID

Robinson Daphne Health Science Policy Analyst, Policy, Planning and Evaluation 

Branch, OD, NIAID

Schneider Johanna Director, Office of Strategic Planning, Initiative Development & 

Analysis, OD, NIAID
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Appendix 2. Analysis of Public Comments to Request for 

Information (RFI) 

NIAID sought input from stakeholders in the scientific research community and the general 

public regarding the proposed priorities through a Request for Information (RFI). The RFI (NOTAI-22-026) was open for comments from February 2, 2022, to April 5, 2022. Comments were 

submitted through a web-based form or by email. Comments were requested on, but were not 

limited to, the following topics in Coccidioides research: 

• Significant research gaps and/or barriers not identified in the strategic priorities above

• Identification of items most likely to facilitate vaccine development

• Necessary resources critical to advancing research in the three strategic areas

• Emerging scientific advances or techniques that may accelerate research related to the 

three priorities

• Approaches to increase marketability of a vaccine and facilitate collaborations with 

industry

NIAID received 13 responses to the RFI, mostly from academia and private companies. Overall, 

the submissions supported both the effort to develop a plan and the specific priorities. No new

priorities were suggested. The comments below provided further details on what to include 

within each priority. 

Input regarding Priority 1—Basic Research 

• Clinical manifestations across racial and ethnic groups

• Clinical differences across the lifespan

• Immune mechanisms underlying various clinical manifestations

• Genetic susceptibility to infection

• Real incidence, including subclinical cases

• Spherulation-specific genes, and mechanism of spherulation

• Immune responses to endospheres, and to early and late spherules 

• Detailed genetic sequencing and annotations, bioinformatics expertise

• Phenotypic variations among strains

• Identify immune responses that are protective and those that contribute to disease

• Role of mucosal immune responses

• Pathogenesis in special patient populations, including pregnant people

Input regarding Priority 2—Tools and Resources

• Simple screening methods: PCR on urine, simple EIA immunodiffusion, skin test for 

chronic carriers
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• Biobanks with blood samples, chest X rays, isolates, tissue samples, with relevant 

clinical information

• Reagents such as cocci antigens and antibodies, recombinant proteins, peptides, 

novel immunogens

• Access to commercial diagnostic tests for research

• Better animal models (especially NHPs) and humanized animal models

Input regarding Priority 3—Vaccines and Therapeutics Development

• Identify correlates of protection for clinical testing (regardless of mechanism)

• Develop cocci-specific fungicides, especially one that enters CNS for meningitis

• Develop post-exposure therapeutics

• Target vaccine against spherules and endospores

• Develop nucleic acid vaccines

• Test new adjuvants, make adjuvants available for preclinical testing

• Define vaccine success: prevent symptomatic pneumonia and disseminated disease 

• Broad protection against several fungi would help commercialization

• Support to test canine vaccine in humans 

• Clinical trial recruitment via military, Dept of Veterans Affairs (VA), ER or urgent care 

The RFI responses reflected the numerous challenges in the development of a Valley fever 

vaccine. The working group members carefully considered all the suggestions and incorporated 

them in the plan as appropriate.
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Appendix 3. Vaccine Development Benchmarks, Criteria, and 

Market Analysis for a Valley Fever Vaccine 

Benchmarks

The Strategic Plan for Research to Develop a Valley Fever Vaccine reflects the fundamental 

research priorities that are necessary to develop a Valley fever vaccine. Supporting research 

aligned with these scientific principles, along with critical research infrastructure, including the

Coccidioidomycosis Collaborative Research Centers, NIAID will continue to advance the vaccine 

development process over the next decade. 

Appendix Figure 1: Benchmarks in the Valley fever vaccine development process.

Vaccine Criteria

To most effectively protect public health, optimal Valley fever vaccines should align with 

specific criteria outlined below. 

A Valley fever vaccine should: 

• Utilize vaccine platforms (and adjuvants) that are suitable for use in 

immunocompromised populations such as recombinant proteins and nucleic acid 

delivery platforms

• Be at least 75 percent effective at preventing symptomatic Coccidioides spp. disease and 

preferably infection 

• Have durable protection that lasts at least 1 year and preferably lifelong protection

• Be suitable for all age groups and special populations, including immunocompromised 

and at risk populations
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Target Product Profile (TPP) Characteristics

Minimal Optimal

Goal Prevent disease Prevent infection 

Age range All adults All ages

Special populations Safe and effective in

immunocompromised

Safe and effective in all 

populations

Species covered C. immitis and C. posadasii C. immitis and C. posadasii 

Durability of 

protection

Lifelong with yearly boosters Lifelong after priming regimen

Vaccine platforms Suitable for use 

in immunocompromised people 

(i.e., recombinant protein, mRNA)

Suitable for use 

in immunocompromised people 

(i.e., recombinant protein, mRNA)

Market Analysis

In 2020, the FDA determined that a significant market may exist for coccidioidomycosis 

preventatives, including a vaccine, in developed nations such as the United States. (Federal 

Register: Notice of Decision Not To Designate Coccidioidomycosis as an Addition to the Current 

List of Tropical Diseases in the Federal Food, Drug, and Cosmetic Act). Although changing 

epidemiology and preferred product profile characteristics may alter these conclusions once 

candidate antigens and candidate products are identified, these findings reaffirm the public 

need for continued advancement of Valley fever research, including the development of a safe 

and effective vaccine. This Notice also underscores the need to continue to engage with 

industry partners as candidate vaccines are identified and progress through preclinical testing. 

In future workshops on Valley fever vaccine development, NIAID will include analyses of factors 

that could impact the Valley fever vaccine market, along with market-shaping tools, such as 

projected cost-effectiveness of a candidate vaccine.
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Appendix 4: NIAID-Supported Valley Fever Research

Resources 

Resource Name Description

BEI Resources Repository Central repository that supplies organisms and reagents 

to the broad community of microbiology and infectious 

diseases researchers

Bioinformatics Resource Centers Collects, archives, updates, and integrates research data 

with user-friendly interfaces and computational analysis 

tools

Coccidioidomycosis Collaborative 

Research Centers

Highly collaborative, multidisciplinary research teams to 

conduct translational and clinical studies for the

improved diagnosis, treatment, and prevention of 

coccidioidomycosis

NIAID Clinical Genomics Program Provides centralized resources to be used for genomics 

and related research

Genomic Centers for Infectious 

Disease Resources

Provides innovative application of genomic technologies 

and rapid, cost-efficient production of high-quality 

genome sequences for pathogens, and hosts

ImmPort Platform to share and analyze immunology data 

generated from human and animal models

Immune Epitope Database and 

Analysis Resource

Database with detailed information for more than 

1,000,000 unique immune epitopes (antibody/B cell and 

T cell) related to infectious and immune-mediated 

diseases

ImmuneSpace Powerful data management and analysis engine for the 

HIPC program that enables integrative analyses and 

visualization of human immunological data

Interventional Agent 

Development

Services to facilitate preclinical development of 

therapeutics and new in vivo diagnostics for infectious 

disease–causing pathogens and/or toxins

NIAID Adjuvant Development 

Program

The goal of the adjuvant development programs is to 

establish and expand the availability of novel vaccine 

adjuvants that researchers can use for preclinical 

vaccine development in both infectious and immunemediated diseases

NIAID Adjuvant Discovery 

Program

NIAID plays a leading role in the discovery, 

development, and characterization of new vaccine 

adjuvants that may be used to: improve the efficacy of 

current vaccines; design new or improved vaccines for 

existing and emerging infectious diseases; and develop 
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Resource Name Description

vaccines to treat allergies, autoimmune diseases, and 

cancer

NIH Tetramer Core Facility Produces and distributes major histocompatibility 

complex tetramers and related reagents to the research 

community

Phase I Clinical Trial Units for 

Therapeutics

Support design, development, implementation, and 

conduct of Phase I clinical trials against viral (other than 

HIV), bacterial, parasitic, and fungal pathogens

Preclinical Models of Infectious 

Disease Program

Provides development, screening, and efficacy testing in 

preclinical infectious diseases models, including 

traditional lab species, nonhuman primates, and nontraditional models

Structural Genomics Centers for 

Infectious Diseases

Applies state-of-the-art technologies/methodologies to 

characterize 3-D atomic structures of molecules to 

support infectious disease research

Therapeutic Development 

Services: Biopharmaceutical 

Product Development Services

Offers services for biotechnology products, such as 

planning, product characterization, process 

development, formulation, Good Manufacturing 

Practice, and Chemistry, Manufacturing and Control 

documentation

Therapeutic Development 

Services: Interventional Agent 

Development Services

Facilitates development of therapeutics, including lead 

identification and development, chemistry and 

manufacturing, toxicology, and pharmacokinetics

Vaccine Adjuvant Compendium Displays adjuvant characteristics or metadata defined 

through NIAID-supported adjuvant studies, helps 

vaccine developers identify suitable adjuvants for 

vaccine indications

Vaccine Development Services: 

Vaccine Testing Services

Offers services for vaccine and adjuvant development 

such as assay development, non-clinical immunogenicity 

and efficacy studies, clinical and non-clinical sample 

testing and safety and toxicity testing

Vaccine Development Services: 

Vaccine Manufacturing Services

Feasibility, Gap Analysis, and Product, Development Plan 

Support, Product Optimization, Process Development 

and Formulation Studies, Product Release Assay 

Development including Potency Assays, Pilot and cGMP 

Manufacture, Audits and Regulatory Activities and 

Documentation, Preclinical Services for vaccines

Vaccine and Treatment Evaluation 

Units

Support efforts to develop new and improved vaccines 

and therapies against infectious diseases