Lymphatic Filariasis Vaccine, Research Paper Example

Specific Aims

The proposed study will evaluate the potential development of a vaccination method for Lymphatic filariasis in order to determine if the host response is sufficient for eradication of the parasite. Filial nematodes exhibit such properties as Interleukin-10 (IL-10) suppression in the host, which quickly compromises the immune system (Dakshinamoorthy et.al 1616). A number of vaccination efforts have been identified in recent years in an effort to eradicate filial nematodes from the host; however, the ability of these nematodes to circumvent these efforts have posed a significant challenge. However, a number of potential vaccination treatments are promising, including the use of Brugia malayi (BmHsp12.6) shock protein as an activator of IL-10 in host cells (Dakshinamoorthy et.al 1616). In conjunction with larval transcript-2 (ALT-2) and tetraspanin large extra cellular loop (TSP-LEL), the potential exists to promote successful multivalent vaccination efforts in rodent models and subsequent human trials (Joseph & Ramaswamy 2). Furthermore, it is known that Brugia malayi alters worm migration in host cells, thereby creating the potential to improve the immune response to these parasites (Arumugam et.al 1). Therefore, the use of Brugia malayi in vaccination development and future testing is worthy of further consideration.

The proposed aims are as follows:

Aim 1: To test a specific hypothesis through the identification of filial nematodes in host cells and determine their path of entry and evasion, including the suppression of IL-10 in these cells as a means of modulating a potential host response to this invasion

Aim 2: To further explore the use of Brugia malayi shock proteins as a potential driving force in overcoming IL-10 host suppression to promote an improved immune response to filial nematode invasion

Aim 3: To evaluate the hypothesis further in rodent model as a means of potential vaccination of host cells and to determine the potential efficacy of this approach for future human testing.

Significance

Lymphatic filariasis is a complex condition that is characterized by filarial nematodes that impact the lymph nodes, and this disease impacts over 120 million people worldwide, with over 40 million experiencing disfiguration as a result (Nagampalli et.al e2662). Through infiltration through the host, patients quickly become immunocomprised, and since these parasites are able to adjust to the host environment and evade possible elimination, they are extremely difficult to eradicate (Nagampalli et.al e2662). Most importantly, the disease is predominantly found in poorer countries where poverty is common; therefore, the potential vaccination of this population is likely to improve health outcomes and reduce health risks within nations where the disease is very common (Nagampalli et.al e2662).

The impact of lymphatic filariasis is so significant in some countries, such as India, that is contributes substantially to gross national product (Hotez). Furthermore, a larger group of neglected tropical disease (NTDs) represent a serious challenge to many impoverished nations, where risk is high and funding is very low (Hotez). Approximately one in 20 persons of the 2.7 billion poorest individuals in the world suffer from lymphatic filariasis, which poses a serious threat to the health and wellbeing of this population over the long term, and also contributes to a high level of risk from an economic perspective (Hotez). The long-standing nature of NTDs also contributes to their high threat level because they are not emerging diseases, which receive greater attention, focus, and funding in many parts of the world (Hotez). As a result, it is widely evident that there must be an expanded focus on lymphatic filaraisis and its vaccination potential for the poor and impoverished throughout the world.

The use of vector management programs in poorer nations has become increasingly prevalent because of the risks that diseases bring to these populations; however, these concerns also lead to significant challenges within these populations that are difficult to overcome and the costs associated with such a program are prohibitive on many levels (van den Berg et.al 89). These factors demonstrate the importance of developing new frameworks for vector management that will attempt to consider the long-term implications of filariasis and its impact on impoverished population groups (van den Berg et.al 89). In addition, it is known that “the challenge in lymphatic filariasis elimination is to reach minimum effective coverage of mass drug administration 25 in annual rounds through scale-up and promotion of compliance; however, there is uncertainty about the coverage level and the number of annual rounds needed to achieve elimination in the local context… As such, where mass drug administration is supplemented by vector control, lower coverage levels and fewer annual rounds would be needed to achieve elimination” (van den Berg et.al 89). With this framework, it is necessary to evaluate the conditions under which vaccination of lymphatic filariasis is feasible and realistic, given the millions of people affected by the condition (van den Berg et.al 89). These considerations play a role in shaping outcomes and in determining the impact of vaccination efforts and their potential risk on the affected populations.

In many cases of lymphatic filariasis, there are significant challenges associated with systemic endotoxemia and intestinal injury, both of which are caused by the disease (Anuradha et.al). In patients with other diseases such as HIV, microbials such as LPS and other markers related to microbial translocation have had a positive impact on the virus, along with specific proteins and cytokines (Anuradha et.al). These factors support the continued growth and development of new approaches to vaccination that may also have a favorable impact on patients with lymphatic filariasis (Anuradha et.al); however, this relationship is associated with patients who already have the disease and not towards prevention methods. As a result, this condition must be explored in greater detail by emphasizing the importance of vaccination methods that may be effective in preventing filariasis in patients who face the highest level of risk, including those residing in poorer nations who live in extreme poverty.

Typically, patients who receive treatment for lymphatic filariasis are administered Ivermectin or diethylcarbamazine and albendazole over a five-year period (Taylor et.al 1178). However, adverse responses to diethylcarbamazine are likely to occur, including pain and inflammation (Taylor et.al 1178). Furthermore, the administration of doxycycline over a six-week period is common to reduce filarial worm presence in the host environment (Taylor et.al 1179). The use of mass drug distribution techniques in Asian countries and in other areas is common practice and is achieved through active surveillance techniques that aim to reduce risk, in addition to community-directed treatment to accomplish the desired objectives (Taylor et.al 1179). These techniques provide a framework for exploring the different areas of the disease that are known to impact large segments of the population in poorer nations, as well as other factors that have a significant impact on patient health (Taylor et.al 1179). Nonetheless, control over the disease is severely limited and requires further evaluation in order to achieve the desired outcomes in prevention, diagnosis, and treatment.

Innovation

It is known that “The inherent complexity of host–parasite and vector–parasite interaction in lymphatic filariasis has restricted our understanding of parasite population dynamics. Within these relationships, density-dependent mechanisms such as vector type, transmission intensity, host immunity, and parasite overdispersion will also affect population dynamics in different endemic settings” (Taylor et.al 1175). Under these conditions, it is expected that the exacerbation of lymphatic filaraisis and its expansion throughout impoverished nations makes it very difficult to eradicate; however, vaccination efforts must be thorough and detailed in order to achieve any possible opportunity to vaccinate over the long term (Taylor et.al 1175).

New innovation in the area vaccine development focuses on specific process steps, including the following: identifying the disease pathogen, developing a diagnostic tool to identify the pathogen in patients, to identify levels of immunity, to identify antigens, to identify any animal models that exist, any potential vaccination prototypes, safety and toxicity studies, clinical trials, and possible regulatory approval. Each of these areas requires significant analysis and consideration and must be conducted in succession in order to achieve the desired results for the target population. The primary source of lymphatic filariasis pathogens is are nematode worms (filariae), which infiltrate the lymphatic system and wreak havoc on its function, thereby causing a host of other conditions, such as edema and genital disease, as well as kidney damage (World Health Organization). These conditions reflect the importance of developing vaccination mechanisms that will be effective in preventing the disease when patients are bitten by mosquitoes, the primary method of transmission (World Health Organization).

The method of vaccination for lymphatic filariasis requires an effective understanding of the modes of transmission and potential treatments that will favorably impact persons at high risk of acquiring the disease. It is now known that “Proof-of-Principle of vaccination against filariae has been demonstrated in animal models with live attenuated and with recombinant and DNA vaccines, and there is considerable knowledge about the mechanisms that underlie vaccine-induced protective immunity as discussed below. This knowledge, combined with the application of post-genomic technologies to antigen identification, analysis and delivery, means there has never been greater optimism nor a better opportunity to develop vaccines against filarial infections” (Babayan et.al 243). Under these conditions, it is expected that there will be additional insight regarding these methods of vaccination through future studies in rodent models that are designed to effectively approach the potential spread of disease through the most at-risk population groups in tropical or high humidity areas.

It is anticipated that vaccination testing for lymphatic filariasis must continue to emphasize advanced models of identification that will support the ability to address the disease more effectively and to recognize the importance of vaccination as a primary disease prevention technique. Patients with the disease may present with a number of key variables, including but not limited to high levels of Th2 response, including an increased level of IgE with low or missing microfilaraemia (Babayan et.al 244). Therefore, these patients exhibit a risk of an elevated inflammatory response, in addition to unresponsiveness in Th1 and Th2 pathways in some patients (Babayan et.al 244). Prior rodent models indicate the presence of an improved inflammatory response when individuals are immunized with irradiation-attenuated infective larvae, but additional models are required in order to accomplish the objectives of full and comprehensive vaccination efforts (Babayan et.al, 244). One limitation to consider with current models is that “the L3 of human filariae cannot mature and produce patent infections in immunocompetent mice, and this has hampered immunological investigations” (Babayan et.al 244). These considerations impact the ability of vaccination methods to achieve the desired level of success without complications that could hamper investigative abilities on many different levels (Babayan et.al 244). It is important to recognize current limitations in research and the ability of individuals to be successful in achieving success with the desired frameworks so that all possible options are explored to improve treatment outcomes for patients in higher risk areas, as these factors play a critical role in shaping outcomes that impact millions of people from the affected population groups who face the risks associated with a poor if nonexistent immune response and a limited understanding of the impact of the disease on the population as a whole (Babayan et.al 244).

Approach

In recent years, there is significant cause for concern that current modes of treatment for lymphatic filariasis may lead to increased resistance in some patients (Babayan et.al 245). For example, the administration of doxycycline to patients may pose a long-term risk if antibiotic resistance becomes a reality (Babayan et.al 245). Furthermore, adverse events associated with DEC and/or ivermectin may lead to complications and discontinued use of these drugs in some patients (Babayan et.al 245). Furthermore, for children under the age of five, ivermectin is not a preferred method of treatment due to its side effects, thereby exposing this population group to a much higher level of risk (Babayan et.al 246). This is a continued focus area for investigators because these children may become the primary mode of transmission for the disease (Babayan et.al 246). These factors support the continued development of new vaccination theories and approaches that will have a lasting impact on the affected populations.

The required approach for this study must explore the appropriate targets for vaccination that will have a lasting impact on host cells, including the potential development of multivalent vaccines (Babayan et.al 250). However, since parasites exhibit a variable response to vaccination efforts, it is difficult to eradicate these concerns with a single approach (Babayan et.al 250). A concept known as parasite-driven immunoregulation must be explored as a potential method to improve Th2 response, but this also requires an improved understanding of parasitic responses in order to achieve the desired impact (Babayan et.al 250). The application of DNA technology to this study demonstrates the importance of developing new directives to facilitate the effective understanding of structural models to encompass future directions in research that will impact long-term outcomes for at risk populations, such as those in poor nations where prevention methods are scarce (Babayan et.al 250). Vaccination efforts, therefore, must be aggressive, yet they continue to be challenging on many levels.

Novel drug targets must be considered that frame the response effort for lymphatic filariasis in important ways. The use of bioinformatics capabilities provide further evidence that modeling drug designs using these techniques may further the vaccination efforts for the disease (Sharma et.al 157). For example, ligand-based drug designing (LBDD) enables a correlation between the target molecule and the novel molecular structure (Sharma et.al 157). Also, structure-based drug designing (SBDD) also provides a framework for understanding a 3-dimensional approach to targeting a protein sequence (Sharma et.al 157). These alternatives may provide further evidence of the need for additional insight regarding creative approaches to vaccination design and development in the coming years.

The adoption of a multivalent vaccination approach is perhaps most promising, as it demonstrates the use of third stage infective larvae of Brugia malayi, which represents up to 90 percent immunity with DNA prime protein influence (Samykutty et.al 12). This strategy has been developed in prior mouse models and must be considered in future studies in order to determine its level of efficacy and safety so that testing is possible in future human trials (Samykutty et.al 12). Furthermore, the use of a model involving transgenic tobacco with Brugia malayi Abundant Larval Transcript-2 (BmALT-2) exhibited favorable immune response to the disease (Ganapathy et.al 1). In the prior study, it was determined that “The immunogenicity of P-ALT-2 was found to be statistically significant at p B 0.05… Further confirmation studies have to be done to test the immunogenicity of P-ALT-2 by challenge studies. Also, analysis has to be done of F1 progeny growing in selection medium with hygromycin for stable ALT-2 integration and expression” (Ganapathy et.al 9). Under these conditions, therefore, it is possible to perform future studies that would essentially duplicate this model in plants as a cost-effective premise to identify the filarial antigen and the ability to replicate the immune response (Ganapathy et.al 9). This process supports the development of a successful framework for the development of new approaches that support plant-based models, accompanied by existing rodent models for further consideration.

According to Shiny et.al (1221), there is a potential advantage of recombinant Wolbachia HSP60 in reducing T cell activation and lymphoproliferation. The use of the Wolbachia antigen may promote the desired immune response; however, the results are unclear (Shiny et.al 1224). Nonetheless, there is a significant advantage associated with the development of exposure of the Wolbachia surface protein (WSP) and its contact with the host immune system (Shiny et.al 1226). Future studies in this regard must address the impact of the regulatory response through immune cell exposure in order to determine receptor regulation levels and blockages of signaling pathways (Shiny et.al 1226). In this context, it is necessary to address these findings more closely as part of a much larger framework that emphasizes the significance of optimizing the immune response to ensure that vaccination approaches are successful.

Future

The development of the proposed vaccination method requires a significant understanding of existing methods and procedures that are designed to facilitate a successful immune response in patients, while also exploring other avenues to support these vaccination efforts. Due to the complexities of the vaccination development process, there are considerable challenges associated with pathogenic immunity, as patients with lymphatic filariasis possess immunosuppressed immunity as a result of the condition and are severely limited in their ability to fight the disease. This suggests that the capacity to create an immune response may be derived from a number of areas, although these factors are difficult to determine.

The pathogenesis of filial nematodes and their invasion of the lymphatic system is complex because these parasites are able to mask their function and influence immunity in different ways, thereby invading the lymphatic system and wreaking havoc on many organs and t the skin. These complexities demonstrate that it is difficult to vaccinate for the parasite because of its multi-faceted capabilities in overcoming the immune response through its highly transformative activities. Therefore, it is important to identify other factors that might contribute effectively in achieving an immune response to the pathogen over time. These methods will support a more comprehensive understanding of the disease and why it is able to mask itself within the lymphatic system and infrastructure. This process is particularly difficult to comprehend due the complex nature of the immune response or lack thereof; as a result, it is necessary to identify areas where there might be additional frameworks in place that will support the expansion of the immune response and reduce immunosuppression in the presence of the antigen.

In order to conduct vaccination testing, two models should be considered in rodents and plants. As prior studies have mentioned, it is important to develop new strategies for improvement that will capitalize on the ability to develop an effective immune response. At the same time, the evaluation of two models will provide further evidence regarding the potential efficacy of the vaccine and its impact on immunity. There are advantages to both models, as the plant model is highly cost effective; however, the rodent model has been explored in prior tests and attempts to mimic the human response. Perhaps the adoption of both models will demonstrate the potential significance and efficacy of the immune response and will provide a basis for exploring concurrent models that may improve the ability to formulate a vaccine with numerous benefits for patients. This process, however, requires further testing, particularly in the plant model, in order to determine if it might be duplicated in human beings in future studies.

If a proposed vaccination method is feasible and has performed well in prior testing involving rodents, and its efficacy and safety have been evaluated, then it is possible to consider future trials involving human subjects in order to determine if the immune response formulated in the vaccine is effective in humans. It is expected that there will be significant opportunities for growth in the development of a vaccination model for lymphatic filaraisis, but exhaustive rodent and/or plant testing must be evaluated more closely prior to testing on human subjects. In particular, the safety and efficacy of the chosen method has not yet been sufficiently proven in the rodent model. Therefore, the efficacy of this model across a wide variety of rodent subjects must be proven before any possible human interaction should be explored so as not to pose unnecessary risks to patients. Future studies must demonstrate that the chosen vaccination method is safe and effective for rodents so that a possible exploration with human subject volunteers will be as safe and effective as possible in future studies that explore this potential even further. Nonetheless, the ability to reach the point of testing in human volunteers may require many years, thereby expanding the current rate of transmission in the poorest population groups who face this risk.

In conjunction with current preventative and treatment methods for lymphatic filariasis, it is important to identify other resources that will support the long-term support of these studies and their impact on at risk populations. Advanced innovative approaches to the disease must be explored in greater detail as a means of improving the immune response and in the prevention of widespread transmission of parasites. However, this process is very difficult and challenging, with multiple levels of support and understanding that have an impact on widespread programs designed to address the millions of people at risk for the disease. The process of evaluating the possible techniques to expand vaccination efforts for lymphatic filariasis requires expert knowledge of the pathogenic mechanisms of the disease and its impact on human beings through transmission by mosquitoes in many dense tropical areas throughout the world where these parasites reside. This mechanism facilitates widespread transmission of these parasites in many human subjects and requires ongoing investigation and research in order to accomplish the proposed objectives. This long-term approach may lead to numerous benefits for at-risk population groups and requires much consideration and testing in order to accomplish the desired objectives. These patterns will support the development of new strategies for improvement that will are likely to have a positive impact on the health and wellbeing of the poorest population groups.

It is anticipated that upon the completion of successful Phase I, II, and III clinical trials, the vaccination method will be evaluated by the Food and Drug Administration and for possible approval. This is the final step in a critical path of drug discovery, testing, and integration into clinical practice that will have significant implications for the treatment of lymphatic filariasis throughout the world. This step is essential to manufacture, market, and sell the vaccination to clinics across the globe to promote greater health, wellbeing, and prevention for patients most at risk for this disease.

Works Cited

Anuradha, R., et al. “Circulating microbial products and acute phase proteins as markers of pathogenesis in lymphatic filarial disease.” PLoS pathogens 8.6 (2012): e1002749.

Arumugam, S., Zhan, B., Abraham, D., Ward, D., Lustigman, S., & Klei, T. R. (2014).

Vaccination with recombinant Brugia malayi cystatin proteins alters worm migration, homing and final niche selection following a subcutaneous challenge of Mongolian gerbils (Meriones unguiculatus) with B. malayi infective larvae. Parasites & vectors, 7(1), 43.

Babayan, Simon A., Judith E. Allen, and David W. Taylor. “Future prospects and challenges of vaccines against filariasis.” Parasite immunology 34.5 (2012): 243-253.

Dakshinamoorthy, G., Samykutty, A. K., Munirathinam, G., Reddy, M. V., & Kalyanasundaram, 1622. (2013). Multivalent fusion protein vaccine for lymphatic filariasis. Vaccine, 31(12), 1616-1622.

Ganapathy, M., Perumal, A., Mohan, C., Palaniswamy, H., & Perumal, K. (2014). Immunogenicity of Brugia malayi Abundant Larval Transcript-2, a potential filarial vaccine candidate expressed in tobacco. Plant cell reports, 33(1), 179-188.

Hotez, P., & Staley, J. T. (2010). Devastating global impact of neglected tropical diseases. Issues.

Joseph, S.K., Ramaswamy, K. (2013). Single multivalent vaccination boosted by trickle larval infection confers protection against experimental lymphatic filariasis.

Nagampalli, Raghavendra Sashi Krishna, et al. “A Structural Biology Approach to Understand Human Lymphatic Filarial Infection.” PLoS neglected tropical diseases 8.2 (2014): e2662.

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

Sharma, O. P., Vadlamudi, Y., Kota, A. G., Sinha, V. K., & Kumar, M. S. (2013). Drug targets for lymphatic filariasis: A bioinformatics approach. J Vector Borne Dis, 50, 155-162.

Shiny, C., Krushna, N. S., Babu, S., Elango, S., Manokaran, G., & Narayanan, R. B. (2011). Recombinant< i> Wolbachia</i> heat shock protein 60 (HSP60) mediated immune responses in patients with lymphatic filariasis. Microbes and Infection, 13(14), 1221-1231.

Taylor, Mark J., Achim Hoerauf, and Moses Bockarie. “Lymphatic filariasis and onchocerciasis.” The Lancet 376.9747 (2010): 1175-1185.

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. “Lymphatic filariasis.” 20 April 2014: http://www.who.int/lymphatic_filariasis/en/