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.

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Three Observations from UN High Level Health Meetings

During the United Nations (UN) General Assembly, two historical High-Level meetings in the realm of health were held addressing ailments that afflict individuals from every corner of this fragile planet. The first UN High-Level meeting on Tuberculosis (TB), focusing on preventing and treating this elusive disease, was held on Wednesday, September 26th which finally put TB in a global spotlight. Additionally, the third UN High-Level Meeting on Non-Communicable Diseases (NCDs), under the theme “Scaling up multi‑stakeholder and multisectoral responses for the prevention and control of non‑communicable diseases in the context of the 2030 Agenda for Sustainable Development,” took place on Thursday, September 27th. World leaders and their ministers, non-government organizations (NGOs), and other stakeholders partook in these crucial meetings to curtail the suffering these various diseases cause. For each of these meetings, governments approved drafts of political declarations that commit countries to follow through with health policy, funding, and a multisector approach to these disorders. The following summarizes key points and commitments from each of the high-level meetings:

UN High-Level Meeting on Tuberculosis

  • A commitment to mobilize $13 billion for universal access to quality prevention, diagnosis and treatment
  • $2 billion for research and development of new drugs, diagnostics, vaccines, and other tools.
  • Commit to provide diagnosis and treatment with the aim of successfully treating 40 million people with tuberculosis from 2018 to 2022 (including 3.5 million children, and 1.5 million people with drug-resistant tuberculosis including 115,000 children with drug-resistant tuberculosis)
  • Pledge of 30 million people (including 4 million children under five years of age, 20 million other household contacts of people affected by tuberculosis, and 6 million people living with HIV and AIDS) to receive preventive TB treatment by 2022
  • Promise to overcome the global public health crisis of multidrug-resistant tuberculosis through actions for prevention, diagnosis, treatment and care, including compliance with stewardship programs to address the development of drug resistance
  • Oblige to consider how digital technologies could be integrated into existing health systems infrastructures and regulation for effective tuberculosis prevention, treatment and care
  • Commit to provide special attention to the poor, those who are vulnerable, including infants, young children and adolescents, as well as the elderly and communities especially at risk of and affected by tuberculosis.

UN High-Level Meeting on NCDs

  • Commitments to reduce NCD mortality by one third by 2030, and to scale-up funding and multi-stakeholder responses to treat and prevent NCDs
  • Health systems should be strengthened — and reoriented — towards the achievement of universal health coverage and improvement of health outcomes
  • Greater access to affordable, safe, effective and quality medicines and diagnostics
  • A commitment to ambitious multisectoral national responses, integrating action on prevention and control with promotion of mental health and well‑being
  • Increasing energies to reduce tobacco use, harmful alcohol use, unhealthy diets and physical inactivity through cost‑effective, evidence‑based interventions to halt obesity
  • To develop a national investment plan in order to raise awareness about the national public health burden caused by non‑communicable diseases and health inequities

While these are not all-inclusive of the commitments between nation states at these two meetings, they highlight the prominent concerns leaders in both the political and health dominion share. However, special attention should be brought to the dialogue held before and after the duration of the meetings. These discussions reveal the true apprehensions that world leaders fear affects their citizen’s health and well-being. The following are three observations from these two UN high-level meetings that may provide some significance in the future battle with TB and NCDs.

1. Is health trending towards being a right rather than a commodity among world leaders?

Before the UN high-level meeting on TB came to fruition, there was a highly controversial commitment in the declaration that concerned high-income countries like the United States. The commitment was centered around access to affordable medications, in particular, generic medications. The concerned countries had expressed reservations about language supporting UN member states’ rights to interpret and implement intellectual property rights in a way that defends public health and encourages access to medicines. Global health advocates believed this point as being essential to equitable access to medications across the world – treating health as a right rather than a product. In the end, health as a right was included into the declaration, through the leadership of South Africa and Médecins Sans Frontières (MSF), despite upsetting these powerful nation states. In addition, at the high-level meeting on NCDs, language was included that stated a similar commitment – to affirm the rights of UN member states to use intellectual property flexibilities to safeguard public health. Although the fight against these two devastating classes of diseases is certainly at the forefront of leaders’ minds, the seemingly endless interchange of health as a right and health as a commodity seems to be finally leaning towards the betterment for humanity – health as a right.

2. Technology and Policy – Finally Uniting to fight TB & NCDs

Throughout the UN General Assembly last week, several reports, policies and studies were released or highlighted that may prove to shape the future treatment of TB & NCDs. The following list are just a few of the major contributions that various sources released:

Health care professionals throughout the world realize that diseases need to be undertaken in a biosocial manner – utilizing both technology and policy. The outcomes that resulted from last week’s reports reaffirm that political leaders realize that the true way to overcome these burdens is to address them through this manner.

3. Multi-Sectoral Approaches – How should they be conducted?

One of the biggest initiatives in global health is the necessity to bring together all stakeholders in disease management in order to properly address the situation. With a vast array of input and ideas, different perspectives, and an atmosphere of collaboration, global health is trending rapidly in this manner – with a significant portion of the world partaking in multi-sectoral approaches already. However, the manner in which these are conducted can vary within countries and between NGOs and governments. Although these remarks may not apply to every country, the following statements made by world leaders may provide some insight into how a country could carry out these approaches:

  • A representative from the Netherlands state that including all stakeholders into the approach may cause conflict of interests – “The days are gone when the tobacco industry has a seat at the table” while also stating “multi-sectoral approaches are good, but governments should be in the lead” in reference to NCDs.
  • An NCD Alliance representative mentioned “it is for governments to determine their own priorities” and “civil society is ready to support, but governments must lead the way.” while simultaneously reaffirming her support for multi-sectoral approaches.
  • Finally, Gerda Verburg, coordinator of Scaling-Up Nutrition Movement explained that “Bigger companies are part of the problem, but we won’t succeed unless we make them part of the solution,” while also adding that she realizes that this is often difficult for civil society, and that “too often, they stand with their backs to the table where we need a critical dialogue with the private sector.” In addition, she supports the priority to “strengthen national systems.”

In a global society where the healthcare landscape is in constant motion, the ability to gather world leaders to commit to significant leaps of change is promising to all those who inhabit this planet. However, these commitments need to be followed up with action, funding, and the political will to properly solve the world’s number one killer and the deadliest infectious disease. The global health community should inspire and encourage their governments while correspondingly holding them accountable to adorn these commitments and continue to battle these overwhelming diseases.

 

Antibiotic Resistance: Hidden Rates in Rural Areas of the Developing World

When the age of antibiotics commenced in the 1950s, diseases and infections that typically would lead to humans being stigmatized by society, a permanent stay at a sanatorium, and then ultimately death were suddenly able to be treated quickly and efficiently. Penicillin and Streptomycin, not only improved a patient’s quality of life and longevity, but reshaped the very nature of treating infectious diseases. Health care professionals now possessed a cure to end the spread of the ailment and to eliminate the actual microorganism that created the suffering. However, these agents brought with them negative consequences that the global health community is still combating today – antibiotic resistance being one of the most significant issues. Antibiotic resistance is the predator’s (bacteria, virus, other microorganism) ability to resist an antibiotic that once was able to eliminate it. Although antibiotic resistance can occur naturally due to the cleverness of bacteria, fungi, and protozoa, the misuse of antibiotics in humans has tremendously accelerated the rate and severity of resistance. This inappropriate use of medicine and skills has led to difficult to treat infections like Extended-spectrum beta-lactamase (ESBL) producing strains of Enterobacteriaceae and even untreatable infections with no known drug on the market able to help an infected patient. The concept of antibiotic resistance often differs within the medical community when comparing the developed world, particularly urban areas, and the developing world, particularly rural areas. The amount of research, minds, and technology mobilized to address this unruly behavior by microorganisms varies drastically between the two sets.

In the urban developed world where physicians are equipped with the most innovative antibiotics known to man like daptomycin or the “Crispr” agents, antibiotic resistance is frequently a topic of discussion along with funding, human resources, and technology available to address it. Also, common ideology is that antibiotic resistance arises from the direct misuse of antibiotics rather than of natural causes. Contrasting the rural developing world, the aforementioned necessities to deter antibiotic resistance are often lacking due to health inequalities that unfortunately are ubiquitous throughout this fragile planet. More interesting though, health care professionals have formed an impression that antibiotic resistance more commonly stems from the dissemination of resistant organisms. With this mindset ingrained in world health leaders, the agenda has been to focus on prevention through this venue in the rural developing world – often lacking a call of funding to determine actual causes of antibiotic resistance and their associated rates in the rural developing world. While the dissemination of strains of Escherichia coli through feces and Multi-drug resistance Tuberculosis through poor air quality certainly needs to be addressed, the Centers for Disease Control and Prevention (CDC) released a report in 1999 encouraging health care professions to consider a range of socioeconomic and behavioral factors including misuse of antibiotics by physicians, unskilled practitioners, the public, counterfeit medications, inadequate surveillance, and political factors. To follow up with this theoretical account, the World Health Organization (WHO) conducted a survey across twelve (12) low to middle income countries across the world in 2015 to interview the population about their beliefs towards antibiotics and resistance. Some of the results are presented below:

  • In lower income countries, it was reported that antibiotic use is higher (42%) than in higher income countries (29%).
  • Across the countries, the range of patients obtaining their antibiotics with a physician’s prescription ranges from 56% to 93%.
  • The percentage of individuals believing they can use the same antibiotic as a family member did to treat a similar illness is 25% while 43% believe it is acceptable to buy the same antibiotic from a local pharmacy.
  • When patient’s start to feel better, 32% of the those interviewed believe they can stop the antibiotics and not follow through with full course.
  • When treating colds and viruses, 62% of respondents believe antibiotics could be used to treat these ailments.
  • Finally, 44% of those interviewed believe antibiotic resistance is only a problem for those regularly taking antibiotics.

These specific social results from patients in the developing world directly conflict with the thought of the major distributor of antibiotic resistance being through dissemination of the disease. The beliefs presented through these percentages seem to lead to a whole host of factors being involved similar to the developed world. In addition to these social results, PLOS Biology released data in 2018 that Escherichia coli was resistant to commonly prescribed antibiotics like ampicillin (92%), ceftazidime (90%), cefoxitin (88%), streptomycin (40%) and tetracycline (36%) in the rural areas of Sikkim, India in pre-school and school-going children. The Journal of the Pediatric Infectious Diseases Society reported similar rates among children in 2015 with Klebsiella pneumoniae having a median resistance to ampicillin with a rate of 94% in Asia and 100% in Africa, and cephalosporins having a rate of 84% in Asia and 50% in Africa. Also, The World Health Organization informed the global community that in Malawi in 2018, nearly 100% of Neisseria gonorrheae genital isolates were non-susceptible to ceftriaxone and roughly 15% were non-susceptible to azithromycin. When analyzing both the social and technical results from above, a renewed emphasis and novel perspective needs to be created in order to properly address antibiotic resistance in the rural developing world.

At the beginning of this year (January 2018), the World Health Organization released its initial reports utilizing an innovative reporting system for antibiotic resistance christened Global Antimicrobial Surveillance System (GLASS). This system was developed in order to preserve human and animal health throughout the globe in relation to antibiotics and their resistance. Although GLASS was officially launched in 2015, it is still in its early implementation period with only 22 countries reporting on actual resistance within their nation states and 40 countries reporting on their national surveillance program. However, GLASS aims at a variety of measures that will ensure antibiotic resistance is more appropriately addressed in the rural developing world by providing a standardized approach to collection, analysis, and dissemination of information to participating countries. GLASS will strengthen nation states antibiotic resistance surveillance systems and modify the data being studied from solely laboratory data to epidemiological, clinical, and population-level data. The preliminary results that were released by WHO revealed that across the 22 reporting countries, there were 500,000 individuals suffering from an infectious disease with antibiotic resistance. Although this data varies with completeness and accuracy across countries, the outcomes highlight the global emergency antibiotic resistance posses from the urban developed world to the rural developing world and everywhere in between – these mutated organisms will fail to respect national borders.

The global health bodies throughout the world have initiated programs and offered advice to nations that will serve the battle against antibiotic resistance well. However, the concealed rates of resistance in the rural developing world will need to be undertaken medically and socially in order to properly end this global emergency. Pipeline innovative antibiotics like relebactam, a novel beta-lactamase inhibitor and an educational emphasis on behavior habits will aid these parts of the world – but the health community will fall short unless the world changes its perception of antibiotic resistance in the countryside of Cambodia, the rice terraces of Vietnam, the jungles of Belize, and areas with similar socioeconomic status.

United Nations High-Level Meeting on Tuberculosis: Importance of drug quality

At the end of next month, the inaugural United Nations (UN) High-Level meeting on Tuberculosis (TB) will take place in New York to discuss the future of the bout against the devastating yet elusive disease. As TB remains the largest infectious disease torturer in today’s society taking the lives of 4500 humans each day, the theme of this occurrence is “United to end Tuberculosis: an urgent global response to a global panic”. This unparalleled step undertaken by governments throughout the world along with those allies engaged in ending Tuberculosis will address an assortment of issues at this meeting. Although the exact agenda has yet to be revealed, the resolution to host this single day meeting mentioned the following items could be discussed:

  • Adequate funding for novel diagnostic testing, medications, and vaccinations
  • Multi-Drug Resistant Tuberculosis (MDR-TB)
  • Responsibility for multisectoral collaboration within nation states, regions, and the globe
  • Universal health care coverage and ensuring tuberculosis coverage is included

Each of these items – ranging from the use of prophylactic low dose isoniazid therapy to equal distribution of the recently designed TB diagnostic test Xpert MTB/RIF – are crucial in accomplishing the END TB strategy laid out by the World Health Organization. However, after looking over these action items for the meeting, Tuberculosis drug quality seems to absent.

As health care professionals across the globe continue to treat TB on a patient specific basis, certain untreated cases occur that puzzle even those who have treated the disease for years. The reasoning behind treatment failure? Adherence to medication or drug resistance are often the first assumed thoughts those sharing their patient’s fate may have. Yet, the actual medicine with its various active and inactive ingredients is often not called into question.

Towards the end of last year, the World Health Organization released an alarming figure concerning drug quality in low to middle income countries. In the report released to the public, WHO stated that approximately 10% of medications are counterfeit in these areas of the world – which happen to be the areas where Tuberculosis and other infectious diseases take their largest toll. In addition, WHO added that this percentage is most likely only a small part of the number of humans truly affected by counterfeit medications. To provide clarification, WHO considers counterfeit medications to be unapproved by regulators, unable to meet quality standards, or purposefully misrepresented active or inactive ingredients in the medication. In addition to this report by WHO, the National Institutes of Health (NIH) published a report outlining in 2015 that 9% to 41% of anti-tuberculosis and other infectious disease medications failed to meet the standards sought in specific studies.

It is vital for the global health community to obtain an effective vaccine to prevent pulmonary tuberculosis, to have a rapid yet specific TB diagnostic test, to create a strategy for various sectors of a nation state to work together in ending TB, and novel agents to treat the most severe cases of MDR-TB. Individuals in rural Kampot, Cambodia, inmates in the Russian prison system, or those residing in the slums of Bangalore, India often can be restored to health through the means that have been available for the last half a century. The RIPE (rifampin, isoniazid, pyrazinamide, and ethambutol) regime has proven its success in treating non-resistant tuberculosis – so long as each of the medications are of appropriate quality. However, The Lancet released a report in January 2017 that found that 8.9% of Indian rifampicin products were of inadequate quality in a country that is burdened with the highest prevalence of tuberculosis across the globe. Moreover, WHO revealed that 28.3% of rifampicin containing medications found in the Russian Federation in 2011 failed to meet predetermined specifications for proper quality – a country known to have one of the highest MDR-TB burdens in the world. With the aforementioned statistics released by the WHO, The Lancet, and NIH, a renewed emphasis needs to be placed on ensuring the quality of each and every tuberculosis medication that reaches a human being. The possibility of one in ten (or more) TB medications being counterfeit will continue to lead to failed treatment regimes, inappropriate use of resources, and spread of MDR-TB even if innovative technology is developed.

In order to combat counterfeit medications on a global level, the World Health Organization developed a reporting system for the interconnectedness of the medication market. The Global Surveillance and Reporting System (GSRS), that all WHO members are eligible to contribute to, aims at collecting data on falsified medications, vaccines and other medical equipment to address real-time situations and prevent further harm. With this reporting arrangement in place, the WHO has reacted and thwarted mortality and morbidity associated with counterfeit medications – including the contaminated cough medication supply that led to 60 deaths in Pakistan and a number of individuals treated with an antidote in Paraguay in 2013. On top of the GSRS, WHO has implemented Good Manufacturing Practices (GMP) that each manufacturer should achieve in order to be certified by WHO; thus, providing a reliable source of medications that nation states can purchase from. Although these initiatives have brought about encouraging results along with halting global medication emergencies, there are still barriers that accompany these programs. The technical training, technology, and adequate staffing to properly identify and report through the GSRS is often difficult to obtain in the developing world while GMPs are often misapplied and have inadequate supervision. The root cause is the long-term development of countries’ public health systems – of which continuing problems with counterfeit medications remains deficiently addressed. A county’s public health care system is the vital organ to ensuring quality medications through these mechanisms that WHO has created and employed. An underutilized and under resourced public health care system leads a budding yet unregulated private market – unable to ensure proper treatment for those seeking it.

Since the United Nations declared this a high-level meeting, meaning all heads of member states are encouraged to participate in the highest level possible, this venue provides the ideal opportunity to recommit to guaranteeing TB drug quality. The sustained empowerment of the public health care systems for those countries tirelessly battling tuberculosis will be a step forward into truly ending this devastating disease. Each health care professional spanning the globe has a responsibility to accompany these governments, colleagues, and fellow humans by investing their time, resources, and talents to develop procedures and systems to ensure effective drug quality.