Repurposing Medications: Reimagining Treatment Options

Last month around the Chinese New Year holiday, a prominent Chinese scientist from Guangzhou Medical University made an announcement that stirred controversy both domestically and internationally while also highlighting a route to combat ailments that global academia and pharmaceutical industries have been attracted to for years. The scientist revealed that his team had been injecting patients with a malaria-causing parasite in order to cure a range of cancers – with two patients seeming to have no cancer cells remaining at the site of tumor and five additional patients having no disease progression out of ten total patients receiving this malarial therapy for at least a year. Although this type of treatment has been attempted in the past in an attempt to combat HIV in the 1990s, the Centers for Disease Control (CDC) and other health governing bodies determined that there was insufficient pre-clinical data to justify human trials during this time period. The controversy revolving around this announcement encompasses the aforementioned determination by CDC, the release of trial results before being published in a peer-reviewed journal, and, most importantly, the possibility of creating a malaria public health emergency for a country due to eradicate the communicable disease by 2020. Although the scientist who underwent this study clearly abdicated internationally conferred health principles, this avenue of repurposing – repositioning, re-profiling, re-tasking, etc – medications and therapy is becoming more appealing to those invested in novel treatment options for both established and emerging diseases.

Throughout the development lifecycle of new chemical entity (NCE), the process for regulatory approval could span over ten to fifteen years with an associated cost of over 2 billion dollars. This has led to an average of only 20 to 30 NCEs being approved by the Food & Drug Administration (FDA) each year. However, through repurposing medications, the development span can be cut to five to eight years at approximately 60% of the total NCE cost – in addition to higher approval rates from regulatory agencies. This repurposing process, as shown by the statistics, is enormously appealing for pharmaceutical companies/investors, but also provides targeted therapy for patient’s disease states at a theoretically lower price than an NCE. Even for rare genetic diseases, repurposing has become common due to only 400 medications being on the market to treat over 7000 genetic conditions. Repurposing is accomplished through the theory of translational research which takes a look at basic scientific discoveries and determining how a medication can be made to match this discovery – for example, examining the molecular pathway of diabetes and then matching it with a chemical entity that has an effect within the pathway like glucagon-like peptide 1 (GLP-1). The known chemical entities are commonly stored in giant databases within academia and the industry. Through big-data analytics, advanced modeling, and high throughput screening techniques, these chemical entities can then be extracted from the databases and determined if it has a possible role in a certain molecular pathway.

This method of establishing novel treatment options ought to be utilized more frequently and effectively, though there are medications over the years that have undergone this type of approval. The following are examples of already approved medications and others undergoing clinical trials:

Approved Repurposed Medications:

  1. Thalidomide, which was originally developed as a racemic mixture of enantiomers for the treatment of morning sickness but found to be teratogenic due to the effect of the (S)-isomer, was later successfully developed by Celgene as a single (R)-isomer product for the treatment of leprosy and multiple myeloma.
  2. Viagra (Pfizer’s sildenafil) was a drug that initially failed as an angina treatment in clinical studies; however, during these trials, its effect on erectile dysfunction was noted and then later approved for this indication.
  3. Celebrex, commonly used in osteoarthritis, works by inhibiting COX-2 receptors. Recently it has been shown that for patients that previously had colon cancer, taking this agent can reduce the risk of additional polyp formation without negative gastrointestinal effects associated with existing treatments.
  4. All-trans retinoic acid (ATRA), which is an acne medication, when combined with traditional chemotherapy, results in complete remission of acute promyelocytic leukemia in 90% of treated patients.
  5. Tamoxifen, a hormone therapy medication, treats metastatic breast cancers, or those that have spread to other parts of the body, in both women and men, and it was originally approved in 1977. Thirty years later, researchers discovered that it also helps people with bipolar disorder by blocking the enzyme PKC, which goes into overdrive during the manic phase of the disorder.
  6. Raloxifene was initially developed to treat osteoporosis, but has since been shown to reduce the risk of invasive breast cancer in postmenopausal women in 2007.
  7. Zidovudine (AZT) was initially developed to treat various types of cancer, but was determined to be ineffective. However, it was repurposed into the first approved HIV/AIDs medications in 1987 and has had a tremendous impact on the progression of the autoimmune disorder.

Repurposed Medications Undergoing Clinical Trials:

  1. The lipid soluble simvastatin is currently undergoing a trial in the UK to assess the efficacy of reducing the progression of Parkinson’s disease. The statin drug class is thought to prevent this ailment through its pleiotropic effects including reducing inflammation, reducing oxidative stress, reducing the formation of sticky bundles of alpha-synuclein, and increasing the production of neurotrophic factors. The results are expected to be released in 2020.
  2. Purdue University received a grant from the National Institutes of Health (NIH) to discover the effectiveness of Ebselen, a chemical entity, against methicillin-resistant Staphylococcus aureus (MRSA), and auranofin, which is FDA-approved for the treatment of unresponsive rheumatoid arthritis, against Clostridium difficile.
  3. Metformin, a first line agent for many diabetics, has been shown to reduce the risk of breast cancer in diabetes patients and is being investigated as a treatment for cancer in many different clinical trials

Although this is certainly not an exhaustible list of the impacts repurposing has had on healthcare, the majority of this repurposing stems from serendipitous observations rather than targeted interventions. Through these unanticipated occurrences, a range of disease states can now be more effectively treated ranging from communicable diseases like HIV/AIDS to mental health ailments including bipolar disorder and Parkinson’s disease to non-communicable diseases. As the rising cost of healthcare continues to devastate humanity and lead to health inequalities, heads of governments, pharmaceutical industries, academia, and nonprofits need to commit themselves into investing their time and resources into this repurposing method. The targeted repurposing interventions are more vital and should be devoted to in order to expand options for health disorders rather than the unexpected observed effects. The financial and health outcomes will lead to novel treatment options accessible to a majority of the world which will allow health care professionals to properly accompany their patients through their disease state.

The Forgotten Health Inequality: Languages and Medical Information

Health inequalities and disparities have plagued this fragile earth since the beginning of unprecedented medical advances, the wealth divide, and the transition from agricultural economies to industrialized states. These health inequalities can range from lack of access to diagnosing technology, unaffordable medications that treat ubiquitous ailments, and distribution barriers that cause a shortage of preventive tools and drugs. Each one of these entities cause an immense amount of suffering for both health care providers, who are required to overcome the barriers, and, for those who are directly afflicted – patients and their families. In addition to these aforementioned health inequalities, the distribution of medical information is directly affected by another concealed yet detrimental form of disparity: the lack of diversity within the languages it is presented in.

Those who inherently speak English won’t face the same barriers as a rural Brazilian physician being unable to fully comprehend English specific instructions for a novel diagnosing tool for the Zika Virus. Nor will those inhabiting anglophone countries endure the same struggle of a Burmese pharmacist who isn’t able to utilize the pharmacokinetic data from a recently approved medication for colon cancer. The fact that information in English related to lifestyle changes for coronary heart disease might not be clear to some community health workers may not be realized from those hailing from the developed world where English is commonly spoken. Treatment guidelines, publications in prominent internationally renowned journals, medication inserts, and countless other resources are typically exclusively published in the English language – creating an insurmountable barrier for those having little access to an English medical education. While having a universal language like English as a connecting tool for the international health community has several benefits, this encompasses a little more than a billion fluent/semi-fluent English-speaking individuals on this earth: leaving about 6 billion humans with little or without access to this rich collection of health information. This language barrier for the majority of humanity amplifies the problems with the quality of care a health care provider is able to administer when also considering other health disparities like lack of access to technology and medications.

This disparity infects and disrupts many facets of the global health communities desire to truly empower local health care professionals and create sustainable public health care institutions. Although the leading global health entity, the World Health Organization (WHO), has attempted to tackle this disparity and expand its impact through diversifying its official languages, it still leaves half of the world population without access in their native tongue. The official languages of the WHO include Arabic (242 million native speakers), Chinese (1197 million), English (335 million), French (76 million), Russian (16 million), and Spanish (399 million) which totals to be only approximately 2.4 billion people. Furthermore, even with these six official languages, only WHO official documents are translated into the six languages while technical reports, guidelines and even the majority of the website is strictly in the English language. Besides WHO and as previously mentioned, the venues novel information is presented in like journals/guidelines is inaccessible to the great majority of health care professionals attempting to provide evidence-based care for their patients. A study published in Deutsches Ärzteblatt International in 2008 revealed that the amount of English-only journals in Medline has risen to 89% with roughly 9/10 new journals with Medline are in the English language. In addition, of 103 journals that are ranked and listed based on frequency of being cited, only 13 are not written (entirely or primarily) in English. This remote information can lead to situations where proper treatment guidelines are not followed causing morbidity or mortality, a lack of awareness of a necessary change within a hospital system, and other negative events that prevents local health leaders from taking charge of their community’s health and creating maintainable interventions.

Although making this medical information accessible to a superior majority of humanity is a difficult task due to lack of awareness, cultural aspects in languages, funding, and human resources, several programs have been recently developed throughout the world to begin addressing this health inequality with the assistance of WHO and political will:

    • In 2009, King Saud bin Abdulaziz University of Health Sciences in Saudi Arabia conducted a study that revealed that just over 4% of all Arabic health information websites met international quality standards. With this data being brought forth, the WHO’s Global Arabic Program was established to disseminate the work of WHO through Arabic publications, make reliable and current health information and research outcomes available in Arabic, and establish networks and knowledge communities in Arabic translation, terminology and publishing. In addition to this WHO program, an establishment of an Arabic health information foundation was created to govern and accredit Arabic health websites and an Arabic health encyclopedia
    • In 2012, WHO established a program, called the WHO Moscow documentation centre, which was funded by the Russian government to increase the number of technical WHO publications in Russian, such as clinical guidelines, and to establish a mechanism for consulting Russian-speaking public health experts on which publications they needed most. In order to ensure proper translation and clinical effectiveness, Russian experts are also invited to review the Russian publications before being revealed. This has directly empowered local health care providers and has provided a sustainable foundation for future Russian health dissemination success.  
  • In 2005, WHO established the ePORTUGUESe program to increase access to health information in Portuguese as part of a collaboration with Angola, Brazil, Cabo Verde, Guinea Bissau, Mozambique, Portugal, Sao Tome & Principe and Timor-Leste. This has allowed each country to develop their own specific health information library to meet specific needs for their populations. This platform can be accessed by anyone with an internet connection, giving health care providers a venue to improve patient care.

These are promising starts to addressing the language barriers that affect health care providers each day while caring for their patients. However, a continued devotion for assisting Khmer-speaking midwives in rural Cambodia utilizing a new birth spacing method, Creole-speaking pharmacists in Haiti checking for drug interactions between coumadin and levofloxacin, and Portuguese-speaking pediatricians in Mozambique deciding what dose of a powerful antibiotic to give needs to be followed through with to honor the global health’s community commitment to each other. While these examples serve as templates for success, an increase in awareness must be brought to the attention of heads of states and health leaders to ensure this health inequality is properly addressed. International health journals have the obligation to better structure their publications in order to make the information more language accessible; while local journals need to promote publications in the residential language to improve the provided health care in the area. The empowerment of public and private health care professionals is vital to the success of their country’s health, and overcoming the medical language barrier is the first step to achieving this.

The Future of HIV: Novel Treatment Options & A Possible Cure

As the medical community and those it serves welcomed in a new year, it brought with it the hope of scientific advancements that will alter the course of certain disease states. These advancements include the use of stem cells to treat to treat macular degeneration, novel microscopic techniques to capture images of the brain, the continued observed effectiveness of the experimental Ebola vaccine, and countless other interventions aimed at creating a healthier global society. Included in these optimisms for 2019 is the possibility for novel treatment options and a possible cure for one of the world’s leading causes of death, HIV. The stories of Timothy Brown – the only individual ever to be cured of HIV, the Mississippi baby and Clark Hawley – both having an extended period of time with undetectable HIV viral load with an interruption of Antiretroviral Therapy (ART), and the Boston patients/Mayo Clinic patient – all three having undetectable HIV viral loads for an extended period of time after a stem cell transplant, have brought much sanguinity to health care professionals and patients alike. However, these exciting results have been unable to be replicated in the majority of the population suffering from HIV and remain unique in their respective occurrences. Although ART has been vital to the HIV community in terms of longevity and quality life, there are still certain populations that are seeking other mechanisms to treat this infectious disease – and, of course, always coveting the idea of a cure. The following is a brief glimpse at the vast pipeline that awaits 2019 and the anticipations of the global healthcare community.  

Combination Approaches

  1. The AIDS Clinical Trial Group (ACTG) is currently exploring the option of combining vorinostat, a HDAC inhibitor along with tamoxifen, which is an FDA approved medication the treatment of breast cancer for postmenopausal women. Utilizing this approach is thought to prevent the reactivation of HIV in CD4+ cells that are latent in addition to increasing the latency-reversal effect of vorinostat through tamoxifen.
  2. Researchers from the USA, France, Germany, Italy, Spain, Switzerland, and the UK are collaborating for a trial testing the combination of two HIV vaccine candidates alongside a monoclonal antibody called vedolizumab. This method of treatment is thought to target a certain protein in the body, α4β7 integrin, that plays a role in transmission of HIV into CD4+ cells. In a macaque model, this combination has shown the control of SIV (HIV but in simians) after discontinuing ART.
  3. At the University of Minnesota, researchers are testing infusions of natural killer (NK) cells with the administration of cytokine interleukin-2 (IL-2). The researchers are hoping to add to the evidence of NK cells being able to exhaust HIV reservoirs and to control virus replication.
  4. In a version of the “kick & kill” method of curing HIV, researchers in Oxford and Barcelona are using a medication to active the latent HIV reservoir while boosting the immune response 1000 times stronger than the usual to rid the body of the virus. Preliminary results showed that 5/15 patients had undetectable viral loads for seven months without ART.

Immunotherapy Approaches

  1. Immunocore, a company founded in Oxford with heavy investment by Bill Gates, has designed T cell receptors that seek out and bind with the HIV virus. These receptors then instruct immune T cells to eliminate any HIV-infected cells, even when the levels happen to be extremely low. Since levels can be rather low in the reservoir of HIV virus that exists in an infected individual, this is a promising lead to completely remove this retrovirus from the body. This immunotherapy has shown to be effective in human tissue samples, but no results being tested in humans have been released.
  2. In France, a company known as InnaVirVax has established a vaccine, VAC-3S, that allows the body to stimulate a production of antibodies against the HIV protein 3S. This, in turn, causes T cells to attack the virus. This is considered a novel approach because it encourages the immune system to recover while equipping it with the tools to continue fighting off the virus. VAC-3S has completed Phase 2a trials, and is partnered with a DNA-based vaccine from FIT Biotech, a Finnish company, that both parties believe can lead to a functional cure.  
  3. In a recently initiated trial, IMPAACT 2008, held in the USA, Botswana, Brazil, and Zimbabwe, a broadly neutralizing antibody termed VRC01 is being investigated for its effectiveness in infants with HIV who are also started on ART within 12 weeks of birth. Although the study aims at establishing the safety profile for VRC01, it is also observing the difference in the HIV reservoir compared with only ART.

Novel Antiretroviral Agents

  1. The manufacturer, ABIVAX, believes it has developed a compound that may help the immune system recognize cells infected with HIV by allowing an increased presentation of HIV antigens on the cell’s service. This would lead to an augmented immune response to abolish these infected cells. This compound has been labelled ABX464 and targets the HIV protein Rev, which is responsible for the transcription of HIV RNA. Reductions of measured HIV DNA have been reported from 25% to 50% in eight of the fifteen patients participating in the study; however, no delay in viral load rebound was found when compared with placebo.
  2. Gilead has created a novel mechanism of targeting the HIV virus through the capsid inhibitors class. Capsids are involved in protecting HIV RNA and related proteins, and capsids also breaks down to release the viral contents into CD4 cells which enable reverse transcription to take place. The novel agent by Gilead, GS-CA1, blocks both the assembly and disassembly of capsids that create non-infectious and defective viruses.

Gene Therapy

  1. Chimeric antigen receptor (CAR) T therapy has been re-initiated in the first cure related clinical trial of this approach in people living with HIV who are on ART. CAR T cell therapy involves the modification of an individual’s T cells that can target antigens of interest. The specific cells modified by the initiative in China, called VC-CAR-T cells, have been modified to target HIV gp120. These modified cells were able to induce the destruction of HIV-infected cells, including latently infected cells exposed to latency-reversing agents, in the laboratory setting.  
  2. With the knowledge of knowing that about 1% of the world’s population is immune to HIV due to a genetic mutation on the gene that encodes for CCR5, US-based Sangamo has begun to edit DNA to introduce the aforementioned mutation. The CCR5 protein is attached to the surface of CD4 cells that allows HIV to enter and infect the cell; with the mutation, it would be impossible for HIV to enter cells. This company extracts patient’s CD4 cells in order to use zinc finger nucleases to edit patient’s DNA to make them resistant to HIV.
  3. Although a highly controversial topic amid the recent publication of the use of CRISPER in twin daughters in China, scientists believe that this tool can lead to a cure for HIV as it is believed to be a much easier, faster, and effective approach than other gene-editing methods. However, the majority of the global health community is in agreement that years of laboratory research and ethical standards need to be established before human trials are properly started.

With the HIV virus adapting and mutating to evade treatments almost as rapidly as the world is producing novel approaches to treating this infectious disease, the drive for continued research and testing should be relentless. These aforementioned examples of novel treatments and possible cures display the creative and diverse thought processes the medical community has put forth to tackle one of the most stigmatized diseases on this earth. However, the ethics behind these trials need to be sound and forthcoming for all of humanity. The trials that occur need to ensure an assortment of demographics including individuals from both developed and developing nations – a subtle form of medical colonialism has no place in the global health community. In addition, trials that enroll patients who willingly accept the benefits and risks associated with the experimental therapy have the moral obligation to supply lifetime treatment if it happens to be effective. The researchers and medical professionals who monitor these participants need to take extreme caution in ART interruptions/discontinuations and certify that the patients realize what complications could transpire due to them. Finally, and most importantly, the interventions that show promise of novel ways to approach HIV or even a cure have to be accessible, affordable, and available to all humans who suffer from HIV. The health inequalities that plague this fragile planet have already been clearly highlighted in this ailment throughout history; the global health community is in debt to humanity for a cure for all when discovered.  

With the global health community’s commitment, the future of the HIV virus continues to transition from infectious disease to chronic disease. While the step that will advance the chronic disease to a cure is still thought to be unknown, the excitement behind the aforementioned gene editing therapy is substantial. The ability to safely, effectively and ethically modify human cells to prevent the entry of the virus into the immune system is certainly the most promising option recently and possibly from this disease’s initial appearance; although, health care professionals haven’t quite figured out how to combine these aspects yet. A cure or even functional cure may be years away, but the global health community needs to continue to accompany those inflicted by this chronic infectious disease to meet the hopes and expectations of alleviating the burdens of HIV.

The Developing World & Non-Communicable Diseases: A Pandemic of Drug Shortages & Inequitable Access

Throughout the developing world, health demographics are rapidly shifting from communicable diseases to non-communicable diseases (NCDs) due to urbanization, lifestyle changes, and introduction of processed food. Although still retaining a significant portion of their communicable disease burden like tuberculosis and malaria, the prevalence of hypertension, diabetes, and cancer in developing countries has increased dramatically and is expected to cause every 7 out of 10 deaths by 2020. With the rise of these health ailments, the global health community has highlighted the importance and severity of these diseases through UN High-level meetings, incorporating relevant indicators in the Sustainable Development Goals (SDG’s), and forming interagency coalitions within countries to address the barriers of NCD prevention and treatment. However, NCD medication supplies have remained an underappreciated barrier that humans affected by global health inequalities confront each day. The complications of drug supplies range from common medications being out of stock to not having a vital class of medications available at the health facility. The medication shortages that plague developing nation states often have a more pronounced effect on underserved populations – essentially causing an impossible barrier to treating their chronic condition and preventing morbidity/mortality.

Last month on November 20thThe Lancet Diabetes & Endocrinology revealed predictions in the year 2030 regarding the world’s insulin supply that stunned health care professionals around the globe. From data gathered recently, the number of individuals diagnosed with Type 2 diabetes is estimated at 405 million people. Although some patients can be treated with oral or injectable diabetic medications like metformin or GLP1 inhibitors, there are approximately 63 million people on earth today that require the use of insulin to manage their diabetes. However, only 30 million individuals use insulin due to availability, affordability, and inequitable access to this essential class of medications. Although these numbers provide a clear indication of the necessity for change in regards to access to insulin globally, the scientists at Stanford that conducted the aforementioned study in The Lancet predicted that the number of individuals diagnosed with Type 2 diabetes will increase to 510 million in 2030 – 79 million of those will need insulin to proper manage their health disorder with only 38 million having equitable access to insulin. These statistics exhibit that, in 13 years, less than half of the people on this planet will be able to access insulin, a medication developed 97 years ago. Though over half of the world’s diagnosed Type 2 diabetics will reside in China, India, or the United States, the study continued and stated that the insulin supply shortage will distress those inhabiting Africa and Asia most significantly. The reasons formulated to explain this health disparity include the fact that three pharmaceutical industries control almost 100% of insulin being manufactured in the world, the complexity of insulin which is a hormone produced by living cells, and generic companies’ lack of interest in producing a biosimilar at an equitable price.   

Cardiovascular diseases (CVDs) pose an implausible health burden on the global society with 30% of all deaths worldwide being attributed to these ailments. Of this mortality caused by CVDs, it is estimated that 80% occurs in the developing world with projections suggesting a steady increase in this percentage. However, with equitable access to cardiovascular medications, approximately 75% of recurrent CVDs can be prevented causing a decrease in both mortality and morbidity for humanity. To determine the access to common cardiovascular medications like atenolol, captopril, hydrochlorothiazide, losartan, and nifedipine, the BMC Cardiovascular Disorders journal published findings in 2010 of a survey within 36 countries. The findings revealed that the drug shortages transcended more complex medications like insulin and affected the access of medications that are considered ubiquitous in the developed world. The analyzed data revealed that of the abovementioned medications in the 36 countries, only 26.3% was available in the public sector and 57.3% in the private sector. The study also stated that in several nations, the wages earned within one working day was insufficient to meet the cost of one day of purchasing treatment. When considering situations where monotherapy is inappropriate, this finding would disclose that treatment would be particularly unaffordable.

When considering access to NCD medications generally, wealth has been a substantial determinant of inequitable access to treatment of hypertension, asthma, cancer, and others classified as NCDs. In many low-income to middle-income countries (LMICs), a wealth gradient has even been observed. In order to gather information to disprove or support this theory, the BMJ Global Health Journal published a study conducted in Kenya in August 2018. The study administered surveys to patients prescribed hypertension, diabetes, and asthma medications and collected data on those medications available at their home, including location and cost of the service. When analyzing the data, the results clearly indicated a wealth gradient for each of the three diseases included in the study in terms of access. As household income increases, so does the likelihood that a family has an opportunity to obtain proper medication. In addition, the results showed that poorer patients had to travel further to obtain treatment than those with a higher income. Finally, and most meaningfully, poorer patients paid more for their medications than their fellow humans inhabiting other parts of the country.  

These global health inequalities are unjustifiable in a global society where the quantity and quality of medications on the market is incredible. The drug shortages and inequitable access differ between the developed world and developing world, but also by socioeconomic stratifications within countries themselves. In order to provide compassionate care to every human suffering from any of these ailments, governments need to begin initiatives to make insulin, losartan, albuterol, and every vital NCD medication available to every citizen in their country. Heads of states, pharmaceutical industries, ministries of health, and health care professionals need to accompany their citizens and patients with a health mindset moving away from health as a commodity to health as a right. Most urgently, universal health care coverage needs to be at the forefront of every national health agenda to properly address this pandemic of drug shortages and inequitable access.

Dengvaxia’s FDA Priority Review: Is the global health community settling on a Dengue vaccine?

The Food and Drug Administration (FDA) announced on October 30th that Dengvaxia’s, Sanofi Pasteur’s dengue vaccine, file has been accepted for priority review within the regulatory agency. With this announcement, the FDA will ensure that a decision will be declared on approval in the United States within six months for the world’s first licensed vaccine protecting against this flavivirus. While this declaration by the FDA displays an improved pragmatic approach to addressing neglected tropical diseases (NTDs), this vaccine has created controversy throughout the global health community. This vaccine is licensed in twenty countries to date and implemented into country wide vaccination programs. However, the concerns accompanying this recombinant, live, attenuated, tetravalent dengue vaccination have led to a discontinuation of this technology with a loss of confidence in several nation states. The Philippines, the first country to complement their vaccination program with this vaccine, has even instructed Sanofi to reimburse the $70 million the country spent to vaccinate 830,000 children. This has caused many global health experts to doubt the impact this vaccine can have throughout the world – causing many to wonder if the global health community is settling on a dengue vaccine.

The dengue virus is estimated to cause 400 million infections each year spanning each of the World Health Organization’s (WHO) regions. This arbovirus belongs to Flaviviridae family and is spread to humans through the bite of an infected female Aedes aegypti mosquito and to a lesser extent from the Aedes albopictus species. The dengue virus has four unique serotypes, DEN-1, DEN-2, DEN-3, and DEN-4, which has caused an effective vaccine to be eluded for centuries. When a person is infected with one certain serotype, the person gains life-long immunity to that serotype. However, if that person contracts a different serotype, it increases the risk of the person developing severe dengue. This phenomenon is called antibody-dependent enhancement (ADE) which allows the different serotype to enter cells more efficiently due to the previously created antibodies from the initial serotype. The symptoms that dengue causes depend on primary or secondary infection. Primary infection results in an acute febrile illness that is typically cleared by the immune system within seven days, while secondary infection can lead to dengue hemorrhagic fever or dengue shock syndrome causing serious morbidity and mortality. The dengue virus currently has no approved treatments – highlighting the importance of an effective and safe vaccine for children and adults alike.  

The significant setbacks for Dengvaxia first arose when Sanofi Pasteur released interim studies concerning children aged 2 to 16 receiving the vaccine who were seronegative. This information was released on November 29, 2017 and revealed that among dengue-seronegative participants, recipients had increased rates of hospitalization for virologically confirmed dengue (VCD) and severe VCD in the vaccine group than in the group not administered the vaccine. These risks were significantly elevated in patients who were aged 2 to 8 years of age and became evident earlier than those aged 9 to 16 years of age. When this data became available, it led to the Strategic Advisory Group of Experts on Immunization (SAGE) of the WHO to reconvene and update their guidance on Dengvaxia. On April 18, 2018, SAGE recommended that for countries considering implementing Dengvaxia, every individual should be screened to determine their serological status with only seropositive persons receiving the vaccine.

The flavivirus genus includes other NTDs including the Zika virus, Japanese Encephalitis, West Nile Fever and Yellow Fever in addition to the Dengue Virus. The symptoms of each these ailments can present almost identically, especially in their milder forms, seeming almost flu-like in nature. When considering these identical disease presentations and the WHO’s recommendation to prescreen individuals for Dengvaxia, health care professionals must turn to dengue serological testing to ensure best practice – if the vaccine is accidentally given to a person with, for example, the Zika virus with no previous case of dengue due to a misdiagnosis from medical history, this would increase the risk of morbidity and mortality if dengue was contracted subsequently. The gold standard for serological testing is isolation and characterization of the virus, like PCR; however, this typically takes six or more days to receive the results and can be burdensome with it’s cost on a public health care system. A more common approach is enzyme immunoassay (ELISA) which is cost effective and less time consuming. However, in areas where two or more of the aforementioned flaviviruses exist, there is IgG cross reactivity between the viruses causing false positives for the dengue virus when ELISA is used. This often rules out the use of ELISA due to a common vector, Aedes aegypti, being able to spread two or more of these viruses within the same zone. Since the dengue virus is endemic throughout the developing world, dedicated health care professionals in these areas often don’t have funds, technology, or training in order to utilize the gold standard, PCR, in dengue testing — further highlighting the health disparities that exist on this earth. This leaves a major barrier to giving proper care to a large portion of humanity including administering this vaccine safely.

With the addition of rapid, accurate dengue test for the serological status of individuals that is in the pipelines (although no estimate of how soon it will be developed has been released yet), this vaccine will certainly find its niche in the global health society. However, this niche will exclude an enormous percentage of humans that would benefit from a safe and effective dengue vaccine. Those individuals that are currently seronegative and those who don’t have access to well-funded public health care system will continue to be at risk for developing the fatal consequences of the dengue virus. Global health leaders need to continue to promote and demand a vaccine that will ensure protection for a greater majority of people. Although this vaccine will serve some well, health care professionals must not settle until the dengue virus and each neglected tropical disease is properly addressed.