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Controlled human malaria infection at the Walter Reed Army Institute of Research: the past, present, and future from an entomological perspective.

Malaria remains one of the greatest infectious disease burdens worldwide, with [approximately equal to] 200 million cases and [approximately equal to] 600,000 deaths reported in 2013. (1) Though not endemic to the United States, malaria incidence is reported in 97 countries, indicating this threat to global health is also a threat to travelers and deployed military personnel. Resistance to drugs that kill Plasmodium parasites (the etiological agent of malaria) is common and spreads rapidly upon introduction. There is no currently available vaccine. Therefore, development and testing of antimalarial vaccines and new drugs has been a top priority for infectious disease research within the Department of Defense for decades.

Plasmodium parasites are delivered to humans by the bite of an Anopheles mosquito; as a female mosquito takes blood from a human host, she deposits the sporozoite stage of the parasite into the host's skin along with her saliva. Sporozoites navigate to the liver where they invade hepatic cells, shift to a new form called the merozoite, and multiply, eventually being released into circulation where they can continue an invade-multiplyrelease cycle, now dependent on erythrocytes. Since the mosquito only deposits about 10 to 100 sporozoites per bite (2-4) and the ensuing life cycle involves exponential multiplication, the pre-erythrocytic sporozoite stage represents a bottleneck in the parasite population that is vulnerable to vaccine and drug activity.

Interventions that specifically target the pre-erythrocytic stage have been in the pipeline since it was first shown that sporozoites elicit an immune response capable of preventing subsequent infection. (5,6) However, as these vaccine and drug candidates were showing efficacy in animal models, it became apparent to medical entomologists that clinical testing of such interventions would require a method of mimicking the natural acquisition of sporozoites by humans via mosquito bite. Previous methods used human gametocyte donors to infect mosquitoes intended to deliver sporozoites to vaccines, (7) but this method was unpredictable and dependent on the availability of people naturally infected with malaria as gametocyte sources. A more controlled, reproducible method was needed; thus, an experimental human malaria infection, later coined as controlled human malaria infection (CHMI), (8) was developed at the Walter Reed Army Institute of Research (WRAIR). The CHMI method encompasses the entirety of a purposeful human malaria infection, from mosquito bite to parasite detection in the blood, to resolution by drug administration. The entomological part of CHMI is considered the "challenge": the transmission of malaria parasites as mosquitoes bite a human volunteer in a safe, reliable, and reproducible way.

IDENTIFYING PARASITES AND VECTORS CAPABLE OF INFECTING HUMANS

To develop a controlled challenge model, entomologists at WRAIR tested the feasibility of artificially infecting lab-reared Anopheles mosquitoes with lab-cultured Plasmodium. A reliable culture method for growing P falciparum in vitro was finally published in 1976. (9) This system became critical for the development of a malaria challenge since it enabled manufacture of parasite lines with known origin and drug sensitivity, followed a somewhat consistent schedule, and used blood and sera of known type that could be tested for pathogens. The downfall of in vitro parasite growth was (and still is) that most parasite lines adapted to grow well asexually in vitro infect mosquitoes poorly, if at all. WRAIR and the Naval Medical Research Institute (NMRI), predecessor to the Naval Medical Research Center, collaboratively tweaked the Trager-Jensen method to grow the best lines for infecting mosquitoes. (10) Foreseeing the need for a compatible parasite-vector pair on which to base the malaria challenge, WRAIR entomologists exposed various anopheline species to multiple P falciparum parasite lines, both lab-adapted and patient-derived, to assay for successful mosquito infection. Although the screening was exhaustive, infection rates were often disappointing, sometimes yielding months of no infectiousness to mosquitoes. By 1983, the 7G8 strain (chloroquine resistant) was cloned from a Brazilian patient sample and, in regular production at WRAIR, showed low numbers of oocysts and sporozoites but with greater consistency than any other strain. In 1985, WRAIR received the African-derived, chloroquine sensitive NF54 P falciparum strain from NMRI which had received it from collaborators in Nijmegen, The Netherlands. (11) This quickly became the primary culture in production. In 1987, WRAIR subsequently received 3D7, a strain cloned from NF54 by NIH researchers, (12) from NMRI. Based on the mosquito infectivity studies done at WRAIR, NMRI, and elsewhere, 7G8, NF54, and 3D7 would become the worldwide standards for cultured parasites suitable for infecting mosquitoes and nearly the only strains of P falciparum used in malaria challenges as of 2015.

For vector selection, the breadth of available parasite strains were fed to a variety of potential vectors, including An stephensi, An freeborni, An balabacensis, An albimanus, An quadrimaculatus, and others. The studies showing 7G8, NF54, and 3D7 were infectious to mosquitoes also showed that An stephensi was a robust mosquito, amenable to mass rearing with hearty feeding propensity, widely used by other mosquito biologists and displayed excellent susceptibility to both P falciparum and P berghei, a pre-clinical rodent model for infection. Therefore, it is not surprising that An stephensi is the primary colony supported within WRAIR and, to date, 3 challenges used An freeborni but the rest have used An stephensi.

INITIAL DEVELOPMENT OF THE WRAIR CHALLENGE MODEL

During vector-parasite compatibility experiments in 1982, exposure of a laboratory worker to an escaped infectious mosquito resulted in accidental transmission of cultured 7G8 P falciparum by lab-reared An freeborni to a human. (13) While this study highlighted the acute need for a safety regimen to safeguard workers' health, it also showed for the first time that parasites grown in culture and capable of infecting a mosquito could also retain infectiousness to humans, inadvertently paving the way for CHMI.

The first CHMI was performed in 1985 as a proof-of-concept trial to assess whether 6 volunteers would develop malaria after being bitten by 5 mosquitoes infected with NF54. (14) Collectively, WRAIR, NMRI, and NIH contributed An freeborni and An stephensi that were given a blood meal containing cultured parasites in donor blood; only blood-fed (and therefore potentially infected) mosquitoes were retained for possible use. At appropriate times, subpopulations were dissected and numbers of oocysts and sporozoites were quantified in midgut and salivary glands, respectively. Mosquitoes determined to likely be infectious were sorted into cups of 5 and allowed access to a volunteer's arm for 5 minutes. Mosquitoes were then checked for the presence of a blood meal (confirmed they fed on the volunteer) and the presence of sporozoites on a 0 to 4 quantification scale (rating of 2 or greater confirmed infectiousness) and, if fewer than all 5 satisfied those criteria, the volunteer was exposed to more mosquitoes until 5 infectious bites were confirmed. This process was performed on a rolling basis--volunteers were called when mosquitoes were ready and not all on the same day. All 6 of the volunteers came down with malaria. This method was independently repeated at the University of Maryland (15) with success (4 of 4 volunteers infected) and the fundamentals of the process are largely how challenges are performed today.

Questions were raised about the validity of using 5 mosquito bites for a challenge. In nature, people are typically infected by the bite of one mosquito; could vaccine-derived immunity be overwhelmed by a 5-bite dosage? And, if so, would a vaccine that would be efficacious against a natural 1 or 2 bite dose be erroneously perceived as ineffective in a 5-bite challenge? Also, how does sporozoite load affect dosage? Compared to natural conditions, laboratory conditions can load mosquito salivary glands with a much heavier burden of sporozoites (16); however, the number of sporozoites successfully deposited in the skin is orders of magnitudes lower than in the salivary glands and highly variable. (3,17) Direct enumeration of sporozoites put into each volunteer is ethically impossible, so 2 challenges were performed by WRAIR for the Navy to assess the feasibility of a 1- or 2-bite challenge. Three out of 5 volunteers receiving a single bite became malaria positive, while 2 of 5 receiving 2 bites became positive. (18) A third 2-bite challenge was performed by WRAIR for Johns Hopkins University with only 1 of 3 volunteers becoming malaria positive. (19) Therefore, a 5-bite challenge has been standard since about 1990. Later studies show that 3 bites from aseptically reared An stephensi can result in 100% infectivity, (20,21) but the consistency and the theoretical advantages of this model have yet to be demonstrated, so WRAIR continued to provide a 5 -bite challenge. In 2012, a series of meetings were held to generate a consensus of all CHMI-capable centers, ultimately agreeing on the WRAIR challenge model of 5 bites from An stephensi using a 0 to 4 rating scale as the global standard. (8)

After 24 years, a second parasite species was introduced to the 5-bite challenge. In 2009, the Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok, Thailand, sent 2 challenges using P vivax in An dirus to WRAIR for infectivity studies. Since P vivax cannot be easily cultured in vitro, the lab-reared mosquitoes were infected with blood from a human gametocytemic patient in Thailand, then shipped to WRAIR for challenge administration. All 12 volunteers from these studies became infected, demonstrating that the challenge model has a measure of flexibility.

VARIATIONS ON THE TRADITIONAL CHALLENGE

Off-site Challenges

Shipping or hand-carrying infected mosquitoes to perform a challenge overseas was initially tested for feasibility in 2000. A batch of prepared mosquitoes was flown from Washington, DC, to London as a mock challenge test of transport and mosquito viability in anticipation of challenges performed by WRAIR personnel for collaborators from Oxford University. This validated the feasibility of a "traveling" challenge that, with slight variations that defer to site-specific clinical trial centers, is performed similarly to in-house challenges. This includes not just the supply of infectious mosquitoes but of dissectors, entomologists, quality assurance/quality control, standard operating procedures, and challenge day methodology that has produced success in the past. This still requires the receiving facility to have minimal insectary infrastructure for mosquito storage but requires no entomological experience, parasite culture, or mosquito rearing on the part of the receiver.

Mosquito Bites as Vaccines

Soon after the debut of CHMI, a second mosquito-biting-humans method was developed, in which volunteers were exposed to hundreds or even thousands of bites from mosquitoes infected with attenuated parasites. At first, this was radiation-attenuated sporozoites as a natural progression from the animal studies and few human studies that already demonstrated this produced a protective immune response. (22) These studies, performed on a rolling basis over several years, would collectively use 23,279 mosquitoes. Later, sporozoites would also be genetically attenuated, (23) but the role of entomology remained the same, differing from traditional challenges in that many more mosquitoes were required and real-time dissections were not necessary. These trials culminated with a traditional challenge to test the efficacy of the mosquito-delivered "vaccine" and/or investigate the immune response generated. Eventually, production of mosquitoes that functioned as a vaccine would be considered by the Federal Drug Administration (FDA) to be a manufacturing process (reviewed later in this article), instituting a sum of regulatory requirements that would impose the greatest modification of the challenge process since inception.

Challenge in a Bottle

Not surprisingly, challenges can be expensive, time-consuming, and require specialized facilities and entomological expertise. Innovations in sporozoite cryopreservation by Sanaria, Inc (Rockville, MD) (24) initiated an effort to overcome these limitations by vialing aseptic, cryopreserved sporozoites into an FDA-regulated product called PfSPZ Challenge, colloquially referred to as "challenge in a bottle." This mosquito-free challenge delivers sporozoites by needle inoculation and is capable of reasonable infectivity rates at a dose of 3,500 sporozoites per vial. This type of challenge is most useful in field settings or locations where facilities cannot support insect maintenance; however, in bypassing the skin, it does not fully mimic the natural route of sporozoite inoculation by mosquito. (25) This means it also bypasses immune responses elicited by skin-deposited parasites in the dermis and draining lymph nodes, and may affect the degree of protection observed. (26,27)

MEETING THE INCREASING NEEDS OF THE CHALLENGE

By 1989, demand for infected mosquitoes, stemming from both clinical and preclinical vaccine research, shifted Entomology into a production role. Every aspect of producing infected mosquitoes, from obtaining enough blood and serum to rearing enough mosquitoes to having the tools and infrastructure to safely handle so many infectious mosquitoes, was reexamined and retooled to meet the needs of CHMI. General rearing rooms were outfitted with specialized equipment to improve insect production and increase efficiency, while smaller equipment such as aspirators to transfer mosquitoes, water jacketed membrane feeders, and mosquito containment devices underwent multiple rounds of innovation to comply with increased demand and increased safety precautions. Mosquito rearing conditions and parasite culture methods were optimized and Entomology personnel began to routinely record data on prevalence and intensity of mosquito infection, no longer as basic research but as indicators of mosquito quality for use in CHMI.

[FIGURE 1 OMITTED]

The biggest physical innovation in mosquito production occurred in the late 1990s as WRAIR moved from downtown Washington, DC, to the Forest Glen Annex in Silver Spring, MD. The insectary facilities in that building were specifically designed to meet the needs of the challenge. The challenge suite exists separate from general insect rearing and consists of (1) an empty vestibule to discourage accidental mosquito release as doors are opened, (2) a main room where volunteers and noninsectary personnel are stationed on challenge day, (3) an adjacent room that houses both walk-in and reach-in incubators for infected mosquitoes, and (4) a separate adjacent room for real-time dissection of mosquito salivary glands. Doors with screens allow personnel to communicate with one another but also contain any escaped mosquitoes in work areas away from the main challenge room where visitors are permitted. Incubator set-up facilitates scale production depending on the sizes and numbers of clinical trials in progress and enable segregation of mosquitoes infected with different parasite lines. The dissection room is designed for the comfort, safety, and efficiency of up to 5 dissectors. A person must pass through 5 doors and a downward air current to get from infected mosquito housing to the main corridor, ensuring the safety of all who work in the building. Two distinct labs specific for parasite culture exist separately from the insectary and other lab space, isolating challenge-specific cultures from general lab work while simultaneously enabling segregation of different P falciparum strains destined for challenges.

The 1990s also ushered in an extensive suite of methodological innovations, transitioning the orientation of challenge preparation from academic to production. Extensive screens for fail-proof stocks of NF54, 3D7, and 7G8 were undertaken, mass sporozoite harvesting methods were adopted, and individualized fine-tuning of each round of parasite culture/mosquito infection was abandoned in favor of a scheduled, standardized culture/ rearing/infection regimen used for every round of production (Figure 1). This was also highly influenced by the advent of new regulatory requirements as discussed in the next section.

REGULATORY INFLUENCE ON THE CHALLENGE

Until 1993, challenges were performed with mosquitoes infected as they would be for routine laboratory experiments. At that time, the FDA became interested in the challenge as a systemized and monitored part of a clinical trial and introduced a wave of new regulatory requirements, exponentially increasing the labor and planning required to carry out each successful trial. A batch master file was created in the fall of 1994 and, within one year, entire cell banks comprised of 140, 110, and 75 vials of NF54, 3D7, and 7G8, respectively, were manufactured under good manufacturing practices (GMP) conditions at the Pilot Bioproduction Facility also located on the Forest Glen Annex. These cell banks, derived from blood collected from clinical trial volunteers, have provided the seed parasites for every WRAIR challenge through 2015, though a new bank was created for 3D7 in 2014 as the original lot dwindled. Every cell bank creation was preceded by months of methodical selection of line isolates that gave robust infection in An stephensi mosquitoes.

The use of infected mosquito bites as a vaccine (reviewed in previous section) precipitated the need to treat infected mosquitoes as an investigational product and to treat anything related to culture, husbandry, and feeding as a manufacturing process. By 2009, production of infected mosquitoes was performed as close to GMP standards as possible for a population of live insects: a library of standard operating procedures were written; the batch master file for parasite production was improved; raw materials and equipment were tracked and certified; forms were added; and each step of the process was documented, reviewed by quality assurance/ quality control (QA/QC) personnel, and filed. These methods were extended to traditional challenges and have become standard.

[FIGURE 2 OMITTED]

SUMMARY OF CHALLENGES PERFORMED

One hundred and four challenges or immunizations by mosquito bite have been performed or are planned through the end of 2015, resulting in over 2200 volunteer mosquito exposures (VME) (some volunteers are counted more than once due to rechallenges or cumulative immunizations on the same person). About half of all challenges have been with the 3D7 strain of P falciparum and another 20.5% were with NF54. 7G8, P vivax, and genetically attenuated parasites with an NF54 background comprise the remainder (Figure 2). All data is summarized from recordkeeping within the Mosquito Biology/Vector and Parasite Biology department within the Entomology Branch at WRAIR.

While the number of challenges performed by year did not remarkably increase until about 2009, the number of VME per year displays a growth trend throughout the 30 year time line. The average number of VME per year for the 1980s is 9.8, for the 1990s is 43.6, for the 2000s is 64.8, and for 2010 to 2015 is 183, with particularly active years in 2014 and 2015 (recorded and projected) (Figure 2). Increase in demand for challenges reflects, first, advancement of vaccine and drug interventions to clinical trials and, second, tentative success of several vaccine candidates leading to follow-up trials to refine dosage, schedule, and durability. This escalation in activity parallels the advent of many organizations with the mission of controlling malaria, such as the Roll Back Malaria Partnership in 1998, the PATH-Malaria Vaccine Initiative in 1999, The Global Fund in 2002, and the President's Malaria Initiative in 2005. Funding from PATH-MVI in particular has directly influenced the increased demand for the WRAIR challenge model to test their sponsored vaccines.

Vaccines as a malaria control intervention has been by far the most common use for the WRAIR malaria challenge model with 61% of all challenges administered for that reason. Another 14% have used the immunization-by-mosquito-bite, primarily by repeated exposure to radiation attenuated parasites. Verification that the model (or modification) is infectious comprised 10% of all challenges, a prudent step before new parasites or changes are made to the model for testing interventions or immunity. As shown in Figure 3, 9% of challenges have been used for research into experimental therapeutics, and several challenges either served a purpose unknown or unique (eg, test of transport and viability overseas).

To date, WRAIR has performed 28 off-site challenges (27%), both domestically and overseas. The remaining 73% were performed in the WRAIR insectary suite as described in previous sections. Exclusive of challenges performed for Oxford University, nearly 65,000 mosquitoes have been used in the CHMIs summarized here (through February 2015). Over 23,000 were used for the irradiated sporozoite vaccinations in the 1990s and over 27,000 were used in irradiated sporozoite vaccination studies in 2014. These numbers denote the numbers of mosquitoes actually exposed to human volunteers. Exponentially greater numbers of mosquitoes are prepared for QA/QC and to ensure mosquito availability is not a limiting factor for CHMI success. Furthermore, up to 10,000 mosquitoes are produced weekly by the WRAIR insectary to support clinical and preclinical malaria research.

CURRENT AND FUTURE DIRECTIONS OF THE WRAIR CHALLENGE MODEL

Although the core of the challenge model has not changed much since the 1980s, the model has improved significantly with new scientific knowledge, applications, technology, and varying needs of users. The next generation of WRAIR challenges anticipates the following variations:

Heterologous Challenge

As vaccine candidates display efficacy against homologous parasites that meets or exceeds the levels called for by the target product profile, demand for heterologous challenges is increasing. NF54 and its derivative, 3D7 are of African origin and serve as the template typically used when designing vaccines. 7G8, a Brazilian isolate, displays a high degree of polymorphism compared to NF54 and 3D7 (28) and is, therefore, an excellent heterologous parasite. However, as observed by labs from multiple institutions, 7G8 is unreliably infectious to mosquitoes. An intradepartmental effort at WRAIR to develop new heterologous strains has evaluated a plethora of field-isolated parasite strains for in vitro cultivation and mosquito infection and, to date, has found none to be dually suitable. Ideally, Entomology would possess a library of heterologous strains from around the world such that parasites with different genetic backgrounds could be tested against vaccines, and those with different drug susceptibility profiles could be tested against candidate therapeutics.

Additional species

Concurrently, the need for challenges using non-falciparum Plasmodium species is rising. Entomology anticipates at least one challenge using P vivax within the next 2 years and more to follow. This encompasses not only late-stage testing of the breadth of protection offered by P falciparum vaccines, but also P vivax-specific vaccines currently in research and development. Despite extensive efforts, P vivax in vitro culture is nearly impossible and existing workarounds (such as constant addition of purified reticulocytes (29)) are incompatible with the challenge model. P vivax-infected mosquitoes can be sourced from AFRIMS, but, as this process uses gametocyte donors, it is not nearly as flexible as what exists for P falciparum. Nonhuman primate challenges (NHP) have also been provided by WRAIR using P knowlesi-infected mosquitoes sourced from partners. (30) In the future, full in-house NHP challenges with P cynomolgi cycled from NHP to mosquito and back are expected at WRAIR. No plans for P ovale or P malariae challenges are in place. Each new tweak to a challenge model requires an investigation into which mosquito species (and strain) is the best to vector the target parasite and how well sporozoites can be recovered, both in terms of prevalence and intensity of infection.

Transmission Blocking Interventions

Vaccines and drugs with transmission-blocking potential should be investigated for efficacy at the clinical level, inciting a need for an inverse challenge: a controlled human-to-mosquito malaria transmission that elevates the standard membrane feeding assay to natural transmission dynamics. Arms of volunteers who received a transmission blocking intervention (TBI) or placebo and who acquire malaria would be offered to mosquitoes for feeding and the efficacy of transmission blocking assessed by Plasmodium prevalence and intensity in those mosquitoes. Currently, most TBIs are still in development, but at least one is moving on to Phase I trials employing this type of methodology.

Dengue Human Infection Model (and Others)

Just as entomologists in the 1980s foresaw the need for a way to test candidate malaria vaccines against natural routes of transmission, it is now obvious that virologists will soon need such a way to test candidate dengue vaccines. CHMI has the distinct advantage of using a pathogen that is susceptible to available drugs and can be completely cured by a simple dosing regimen. This is not a characteristic of other vector-borne diseases that need a CHMI-like challenge to properly test vaccine candidates.

A controlled challenge for dengue is the most pressing need, but it would present ethical considerations (ie, if the vaccine is not protective, you can only provide supportive care, not cure, to a volunteer). From the entomological point of view, CHMI presents an excellent template in which to substitute other mosquito-borne pathogens but with careful consideration of where the processes differ biologically. Dengue human infection model (DHIM) requires a different mosquito species, Aedes aegypti, which displays high variability in vector competence across strains that is often dependent on the specific virus strain used. (31, 32) A suitable Ae aegypti strain would have to be validated for every viral strain desired in challenges. Dengue virus prevalence and intensity cannot be determined in real-time similar to the confirmation of malaria sporozoites via light microscopy, so DHIM would rely on either pre- or postscreening of mosquitoes for positive infection. Additionally, the number of bites optimal for guaranteeing dengue transmission while avoiding overwhelming the immune response would require investigation. The feasibility of such a challenge and some theoretical design elements were reviewed by Mores et al. (33)

SUMMARY

Controlled human malaria infection is a powerful tool in antimalarial testing that requires or benefits from mimicking the natural route of infection. All of the leading pre-erythrocytic vaccines have been tested using this model, and even after 30 years its utility is still increasing. Preparing infected mosquitoes for a challenge is a task that forces a complex and tenuous biological interaction into a manufacturing-style operation of precision and predictability. The challenge portion of ChMI as it exists at WRAIR today is the result of decades of research and refinement. Such cumulative effort is reflected not only in how well the challenge has performed historically but also in the ways that it can adapt to answer new questions about malaria and vector-borne disease.

ACKNOWLEDGMENTS

We thank Dr Imogene Schneider, Dr Jack L. Williams, Dr Claudia Golenda, and MAJ Jittawadee Murphy for their leadership in the Mosquito Biology/Vector and Parasite Biology Department during the development and execution of the WRAIR malaria challenge model. We are very grateful to the dozens of Entomology researchers and staff members who have carried out the 30 years of work described here. We also thank Dr. Frank Klotz for fruitful and engaging discussion about past CHMIs.

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Lindsey S. Garver, PhD

Megan Dowler

MAJ Silas A. Davidson, MS, USA

AUTHORS

Dr Garver is a Malariologist in the Vector and Parasite Biology Department, Entomology Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland.

Ms Dowler is a Biologist in the Vector and Parasite Biology Department, Entomology Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland.

MAJ Davidson is Chief, Vector and Parasite Biology Department, Entomology Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland.
Figure 3. Proportions of challenges performed for indicated
purposes.

Other           4%
Unknown         4%
Drug            9%
Infectivity    10%
Immunization   14%
Vaccine        61%

Note: Table made from pie chart.
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