The Poliovirus Endgame: Create Innovative Ways to Accelerate, Sustain, and Monitor Eradication (Round 7)
Although delayed, the progress made by the Global Poliovirus Eradication Initiative in reducing the incidence of disease caused by poliovirus has been extraordinary. This has been primarily due to the widespread use of the easily-administered oral poliovirus vaccines (OPV).
The effort to complete eradication, however, has met with a number of challenges for which solutions are not readily available. In particular:
- OPV and other orally administered enteric vaccines have shown reduced efficacy in children living in certain resource-poor environments;
- The interactions between OPV, live attenuated rotavirus vaccines, and other enteric vaccines are unclear. In particular, the existence, extent and potential mechanisms of vaccine interference are poorly characterized; and whether protection from diarrheal disease by rotavirus vaccine can enhance OPV efficacy is uncertain;
- Paralytic poliomyelitis incidence currently serves as a surrogate measure for the circulation of wild poliovirus in a region. However, as eradication nears the signal provided by paralytic disease will be eventually lost; new methods to monitor poliovirus circulation are increasingly necessary;
- Improvements in water and sanitation infrastructure are considered to be effective interventions for reducing poliovirus transmission; however, the true impact and relative importance of these measures in limiting transmission remain unclear.
Once eradication of wild polioviruses has been achieved, a number of challenges will remain:
- OPV can, in rare instances, cause vaccine-associated paralytic poliomyelitis. Furthermore, OPV is excreted in the stool and, though initially attenuated, can regain characteristics of wildtype neurovirulence and/or transmission—resulting in circulation of vaccine-derived poliovirus (VDPV) and outbreaks of poliomyelitis;
- Thus, post-eradication, OPV use must cease. However, risks of re-introduction of polioviruses into the population will remain. These risks include persistent shedding of viruses by immunodeficient individuals; escape of OPV or wild virus from containment facilities, laboratories, or manufacturing sites; and bioterrorism. Further, current plans for control of a wild or vaccine virus outbreak in the post-eradication period call for use of OPV, running the risk of generating new VDPV outbreaks;
- Therefore, routine use of the inactivated poliovirus vaccine (IPV) is being considered as a means of ensuring any re-introduced viruses do not spread. However, administration of the current IPV is accompanied by a number of challenges, as follows:
- Manufacturing of IPV currently requires wild virus, thus introducing the possibility for escape of wild virus from manufacturing facilities;
- The delivery and administration of the current IPV requires more infrastructure than that of OPV (e.g., trained medical staff, needles, medical waste, etc.), and will thus be far more expensive and difficult to deploy using current approaches;
- Currently, per dose, IPV is more expensive than OPV (due to both the cost of manufacturing and the scale of production).
- Unlike OPV, the current IPV does not induce strong mucosal immunity in the intestinal tract; thus, IPV less-effectively prevents viral shedding. Post-eradication, re-introduction of wild poliovirus might result in widespread transmission through an IPV-vaccinated population due to intestinal infection and shedding.
What We Are Looking For:
The goal of this topic is to solicit innovative approaches to address the roadblocks listed above. We seek proposals that may be "off the beaten track" and daring in premise, and are clearly differentiated from approaches currently being developed or employed. Proposals must (i) have a testable hypothesis, (ii) include an associated plan for how the idea would be tested or validated, and (iii) yield interpretable and unambiguous data in Phase I if they are to be considered for Phase II funding.
Specific examples to be considered include:
- Studies that provide answers to key questions about poliovirus pathogenesis and will have a direct impact on vaccine design and/or delivery. For example, these may address-
- the impact of poliovirus-stabilizing and destabilizing influences (e.g., exposure to external aqueous environment and the host’s enteric mucosa) on viral entry mechanisms, infectivity, and fitness;
- the relationship between the fitness of polioviruses and their immunogenicity;
- the effect of poliovirus mutations (or recombination events) known to influence cell receptor usage (hence viral fitness) on the capacity for neurovirulence;
- the impact of immune selection pressure on the diversity (heterogeneity) and fitness of poliovirus populations;
- the determinants and consequences of local (e.g., oropharynx, gut) vs systemic poliovirus replication;
- the viral, host, and environmental determinants of transmission via fecal-oral vs respiratory transmission, and the consequences of each;
- immune effector mechanisms other than neutralizing Abs that are involved in (local and/or systemic) control of poliovirus replication;
- the ways in which the above differ for each of the poliovirus serotypes.
- Novel or improved vaccines:
- New approaches, which are practical, scalable and affordable, for improving the immunogenicity and effectiveness of poliovirus vaccines in children living in resource-poor regions where oral vaccine efficacy is reduced;
- Novel ways to substantially increase the level of intestinal mucosal immunity induced by IPV in order to prevent viral shedding;
- Studies aimed at determining direct and indirect functional interactions among rotavirus, poliovirus, and other enteric vaccines.
- Vaccine delivery/formulation:
- Novel approaches to formulate and administer IPV that do not require trained medical personnel or hypodermic needles for administration, provide substantial dose sparing, and lower the overall cost without compromising efficacy.
- Vaccine manufacturing:
- Novel methods to produce an equally or more efficacious inactivated or subunit poliovirus vaccine that do not require wild virus for production and can be manufactured at scale in a cost-effective manner.
- Immunological assays:
- Novel, non-invasive methods to measure poliovirus vaccine-induced mucosal immune responses (humoral and/or cellular) that correlate with reduction in virus shedding;
- Original studies examining factors/processes involved in the waning of mucosal intestinal immunity and methods/interventions for counteracting these factors/processes.
- Novel and sensitive tools to detect polioviruses in environmental or biological samples and determine whether they are wild polioviruses, poliovirus vaccine strains, or VDPVs.
We will not consider funding for:
- Modifications, similar to those already being undertaken, of Sabin vaccine strains for use in IPV production;
- Improvements in cold-chain technology/processes;
- Educational programs, community-based interventions, or other interventions focused on behavioral modifications;
- Advocacy initiatives or policy studies;
- Antiviral discovery, development, or implementation;
- Surveys of sanitation conditions in resource-limited settings that are not directly linked to data that accurately report or test OPV efficacy;
- Implementation of sanitation/decontamination approaches;
- Regional surveillance/monitoring;
- Epidemiological or burden of disease studies;
- Conventional, indirect measures of mucosal immunity (e.g., circulating IgA antibodies), invasive measures, or measures that do not provide a direct comparison to protection from shedding;
- Modified delivery methods for IPV that require skills greater than are currently required for administration of OPV in the field, represent incremental modifications of hypodermic administration, or do not have the potential for substantial dose sparing or production at scale;
- Incremental modifications of existing approaches;
- Studies without specific, testable hypotheses.
Grants will be selected on ability to create impact in the context of our existing global health priorities. For more information on The Bill & Melinda Gates Foundation's priority global health conditions, please click here.