Lymphatic Filariasis Vaccine, Research Proposal Example

Introduction

Lymphatic Filariasis is a devastating infectious disease that affects up to 1.4 billion people throughout the world and causes disfigurement in many patients, due in large part to its severe impact on the lymphatic system (World Health Organization, 2014). The disease is classified as a neglected tropical disease and devastates many poor, rural communities in developing nations because of its relative ease in transmission through mosquitoes who carry one of three different types of nematodes (World Health Organization, 2014). The serious and urgent nature of the disease requires significant attention and focus at the clinical level in order to ensure that those who are most vulnerable are able to prevent its spread as best as possible. A comprehensive strategy requires immediate attention so that patients at the highest risk of exposure to the bacteria receive all possible preventative measures, including vaccinations, which may be effective in reducing these risks. Establishing a successful vaccination strategy for Lymphatic Filariasis is essential because the lack of support, resources, knowledge, and understanding of the cause and nature of the disease in many poor countries are very high. The epidemic nature of Lymphatic Filariasis contributes to low quality of life and poor outcomes for those at risk of the disease, including extreme pain and suffering for many patients. Therefore, urgent attention to vaccination protocols is required because this is likely to contribute to positive outcomes for the highest risk population groups. Since vaccination concepts are severely limited, a new vaccination protocol has the potential to achieve great success in the most urgent populations where the need is greatest and is most pronounced. However, a greater understanding of this protocol is essential to the expansion of clinical trials and testing to determine its efficacy in the most urgent population groups.

Specific Aims

Due to the severe nature and number of cases of Lymphatic Filariasis in many poorer nations, the development of a successful and sustainable vaccination protocol is of the utmost importance to populations who face reduced immunity and lower levels of support to meet their healthcare needs. Due to the high risk of disability and disfigurement for this population, it is important to identify a vaccination protocol that will alleviate economic challenges and health concerns that are directly related to the disease in the affected populations (Samykutty et.al, 2010). For patients who have the disease, there are options available for drug therapy to combat its most significant effects; however, drug resistance may pose a serious problem for those who have access to treatment (Samykutty et.al, 2010). As a result, possible vaccination protocols have been considered that may have a significant impact on the affected populations, including multivalent solutions that require testing via mouse models (Samykutty et.al, 2010). A feasible vaccination protocol is necessary in the short term to prevent additional cases of pain and suffering from the disease. The proposed objective will initiate the development of a vaccination protocol that is cost effective to produce and to purchase, and may have the potential to promote greater immunity within the affected populations on a larger scale (Samykutty et.al, 2010).

The primary objective of the proposed study is to aid developing countries in eliminating Lymphatic Filariasis through the following specific aims:

• To investigate a multivalent approach using a combined method of BmALT-2 and BmHSP to stimulate an immune response that will be effective in reducing the risk of infection (Samykutty et.al, 2010)
• To identify a gender-based genetic approach to the development of potential vaccination protocols to promote greater disease prevention in patients with the highest level of risk (Li et.al, 2011)
• To test the vaccine in one or more animal models for efficacy so that there are sufficient opportunities to address vaccination in a timely and efficient manner to reach as many people as possible

Significance

Lymphatic Filariasis is categorized as a neglected tropical disease that is caused by one of three nematodes and may lead to severe disfigurement, disability, and extreme pain in patients. Millions of people are at risk for the disease in developing countries, and it is commonly transmitted through mosquito bites (World Health Organization, 2014). Currently, 120 million cases of the disease have been reported in endemic countries, with an additional 1.4 billion at the highest risk in countries such as Bangladesh, Ethiopia, India, Nigeria, and Indonesia, among others (World Health Organization, 2014) Control over the disease may be achieved through immunization, which may have a lasting impact on endemic populations yet requires urgent protocol development in order to eradicate the disease. However, vaccination protocols continue to be challenging on many levels and require further consideration and evaluation in order to accomplish the core objectives of increased immunity and greater control over the disease and its long-term devastating effects on the human population (Babayan et.al, 2012).

The disease is primarily caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori, all of which contribute to evidence of symptoms in affected patients (Li et.al, 2011). The potential exists to develop a gender-associated gene protocol that may interfere with reproduction of these nematodes, thereby preventing transmission through mosquito larvae (Li et.al, 2011). However, this process remains advanced and very challenging on many levels, due to its highly specific nature and requires further genetic investigation (Li et.al, 2011). Prior animal studies conducted by researchers at Washington University School of Medicine used B. malayi worms and were divided into male and female forms, and RNA isolation was established using microarray fabrication to evaluate transcription (Li et.al, 2011). The study results indicate that there were sufficient means of identification of gender-specific behaviors, noted as follows: “genes that are differentially expressed in male and female filarial worms potentially encode proteins that are essential for many activities including metabolism, adaptation to the mammalian host, immune evasion and (especially) reproduction” (Li et.al, 2011). Under these conditions, therefore, it is possible to develop a gender-specific vaccination protocol that could favorably disrupt reproduction of specific nematodes (Li et.al, 2011).

The immune response in patients who face the risk of lymphatic filariasis must be well understood. For example, increased levels of immunity related to specific antigens have been established as possible contributors to the immune response and correlate to the potential understanding of HLA antigens as a key component of this process (Hise et.al, 2003).Through specific genotyping, it is possible to determine if genetic changes exist that impact the immune response to the disease, while also considering other options that may pose a threat to specific populations through a higher rate of infection in specific geographic areas throughout the world, such as Papua New Guinea (Hise et.al, 2003).

Identifying a successful vaccination protocol requires an effective understanding of the immune response in humans; for examples, some patients who represent with the most severe symptoms are also characterized by high Th2 and IgE levels (Babayan et.al, 2012). In a prior mouse model, L3 larvae that have been irradiated promote an immune response; however, challenges remain with this approach that require further investigation (Babayan et.al, 2012). Most importantly, “there is clear evidence that the parasite-driven immunoregulation plays a central role in the parasitological outcome of filarial infections and that both innate and acquired responses are under the influence of the regulatory networks that determine clinical outcomes” (Babayan et.al, 2012). As a result, new targets are necessary in order to determine the most effective immune response, using modern techniques and strategies that will encompass new directions in immunological research using this model (Babayan et.al, 2012).

Prototype vaccine

In order to accomplish the desired objectives, it is important to identify a prototype vaccine that will be effective in enhancing immunity for larger population groups who are affected by the disease in significant numbers. This process requires an effective understanding of the ability to identify vaccination targets that will demonstrate a high degree of effectiveness and innovation in order to ensure that optimal immunity is achieved throughout the life span (New England Biolabs). Using genetic approaches, there is a high level of potential associated with the creation of models that utilize specific targets through the use of bioinformatics analysis (New England Biolabs).

Innovation

Due to the challenging nature of Lymphatic Filariasis and the high risk of the disease, I believe that the most feasible alternative at this stage is to conduct Lymphatic Filariasis immunization in a mouse model in order to demonstrate its efficacy and level of success within a given population. Although antibiotics are available to address the infection in the short term, they possess a high risk of antimicrobial resistance within this population (Samykutty et.al, 2010). In the 21^st Century, the development of a feasible vaccination protocol for Lymphatic Filariasis is both critical and achievable, using approaches that include gender-based genetic variation or multivalent strategy to promote greater immunity against the disease. There are potentially significant advantages associated with the use of advanced technologies such as molecular engineering and systems biology in order to accomplish the desired objectives and to recognize the value of developing new frameworks to develop effective models for consideration and testing (Babayan et.al, 2012).

Approach

Based upon the critical need for a feasible vaccination protocol, the following steps are required as a primary approach to ensure that the chosen protocol is successful in its mission:

Evaluating the potential for a multivalent vaccination protocol

The primary concern associated with a vaccination protocol for Lymphatic Filariasis is to identify forms of protective immunity. Most importantly, it is evident that BmALT-2 and BmHSP must serve as primary targets for vaccination development and must demonstrate a high level of immune protection in a mouse model format (Samykutty et.al, 2010). From this perspective, it is believed that vaccination in a mouse model will produce IL-4 at high levels in spleen cells, thereby increasing the potential for similar vaccinations in human models in future testing (Samykutty et.al, 2010). These promising results indicate that it may be a viable alternative to facilitate a potential vaccination protocol for those at the highest risk of contracting the disease.

Developing an effective Lymphatic Filariasis vaccine based on gender-specific genes

The study would also consider the use of gender-specific genes in targeting the reproductive activities of the nematodes primarily responsible for causing infection in humans through mosquito larvae (Babayan et.al, 2012).

Chemotherapeutic Drug Targeting

A proposed study must also evaluate the conditions under which vaccination protocols might consider chemotherapeutic drug targeting as a means of expanding knowledge regarding the immune response and how it might be affected by these targets (Sharma, 2014). This strategy, however, requires further testing and evaluation in order to accomplish the intended objectives and to determine how specific drug targets might contribute to enhanced immunity within specific patient populations who are affected by the disease and experience its most severe symptoms.

Measurement of protective immunity

The complexity of the vaccination protocol requires a detailed understanding of immunization through the use of advanced technologies that will have a positive impact on the immune response (Keiser & Nutman, 2002). For example, “control efforts might be further aided by an understanding of life cycle progression in the insect vector” (Keiser & Nutman, 2002, p. 1). In this context, it is necessary to establish an expansion of protocols to address the larval stages that may have the most significant impact on outcomes (Lok & Abraham, 1992). From this perspective, it is likely that there will be significant opportunities to address investigations regarding larval growth and how this process impacts human immunity in different ways that will demonstrate a high level of understanding of the animal response (Lok & Abraham, 1992). Similarly, these models could be applied to human beings, and in particular, how children respond to the disease in different ways that impact their immunity at a young age (van den Berg et.al, 2012).

Future Plans

The Implementation of Safety and toxicity studies

Once finalized, the proposal will be presented to introduce the vaccination protocol as the primary first line of defense for the prevention of Lymphatic Filariasis infection. Another step to the process will involve a clinical trial upon approval from the FDA and will be conducted in India, Nigeria, and Ethiopia, all of which have high numbers of cases of the disease. However, prior to human testing, an advanced animal model, such as dogs, will be used to demonstrate the safety of the vaccine and also to provide further evidence of its efficacy in the affected population.

During Phase I, the safety of the vaccine will be identified, as this phase includes a small number of healthy, uninfected volunteers who face a very low risk of Lymphatic Filariasis infection, as the testing protocol to determine the safety of the proposed vaccine, using a control versus placebo format. A Phase I trial will offer preliminary data regarding dosing and administration that will contribute to the most effective immune response, while Phase II will determine the efficacy of the vaccine and will include a lower number of volunteers to identify the immune response. Upon the success of the Phase II trial, a Phase II trial will include several thousand high-risk volunteers to evaluate the effectiveness of the vaccine in preventing Lymphatic Filariasis infection.

Distribution, Access, Acceptance

To promote greater disease control, asymptomatic patients must also be considered as part of the process of determining the scope and significance of the disease in the affected population groups.

The proposed vaccination protocol would be presented to the WHO for worldwide distribution, once it has been proven safe and effective via two separate animal models. The target population will include patients with Lymphatic Filariasis. Once prepared and approve, the vaccine should be readily available in developing countries and for populations in need. This approach will be supported by a tiered pricing strategy that is affordable and feasible to promote greater control of the disease in countries where the need is greatest. This process will also provide a basis for conducting expanded education and outreach to the affected populations so that they begin to experience a greater sense of relief and a lower risk of contracting the disease through mosquito contact, based upon higher levels of immunity that impact outcomes for patients.

Works Cited

Babayan, S. A., Allen, J. E., & Taylor, D. W. (2012). Future prospects and challenges of vaccines against filariasis. Parasite immunology, 34(5), 243-253.

Hise, A.G., Hazlett, F.E., Bockarie, M.J., Zimmerman, P.A., Tisch, D.J., & Kazura, W. (2003). Polymorphisms of innate immunity genes and susceptibility to lymphatic filariasis. Genes and Immunity, 4, 524-527.

Keiser, P.B., & Nutman, T.B. (2002). Update on lymphatic filarial infections. Retrieved from http://www.filariasis.net/pdfs/curr_infect_dis/keiser_nutman_2202.pdf

Li, B. W., Rush, A. C., Jiang, D. J., Mitreva, M., Abubucker, S., & Weil, G. J. (2011). Gender-associated genes in filarial nematodes are important for reproduction and potential intervention targets. PLoS neglected tropical diseases, 5(1), e947.

Lok, J.B., & Abraham, D. (1992). Animal models for the study of immunity in human Filariasis. Parasitology Today, 8(5), 168-171.

New England Biolabs, Inc. Combating neglected diseases – genomic approach to identify Potential drug targets. Retrieved from https://www.neb.com/tools-and-resources/feature-articles/combating-neglected-diseases-a-genomic-approach-to-identify-potential-drug-targets

Samykutty, A., Dakshinamoorthy, G., & Kalyanasundaram, R. (2010). Multivalent vaccine for lymphatic filariasis. Procedia in vaccinology, 3, 12-18.

Sharma, B. (2014). Lymphatic Filariasis and Chemotherapeutic Targets. Biochem Anal Biochem, 3, e147.

van den Berg, H., Kelly-Hope, L. A., & Lindsay, S. W. (2013). Malaria and lymphatic filariasis: the case for integrated vector management. The Lancet infectious diseases, 13(1), 89-94.

World Health Organization (2014). Lymphatic filariasis. Retrieved from http://www.who.int/mediacentre/factsheets/fs102/en/