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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Malaria-2015 and beyond

One of the mosquito-borne illness (we have been hearing about these a lot lately in the news, heard of Zika virus anyone?) that the global community has been trying to eradicate for a long time now is malaria. Malaria is caused by Plasmodium, a parasitic protozoan, that is transmitted from the bites of infected female anopheles mosquitoes.

Early this month, the WHO released a video describing the progress that has been made toward reducing/eradicating malaria globally and the challenges that exist in the fight against malaria. The disease is widespread in Sub-Saharan Africa, Asia and Latin America. 214 million cases were reported in 2015. A multi-pronged approach of coordinated responses that include timely diagnosis through Rapid Diagnostic Testing (RDT), treatment using artemisinin-based combination therapy (ACT), distribution of long-lasting insecticide-treated bed nets (LLIN) and targeted insecticide spraying, the global mortality rates have decreased by 60% between 2000-2015. The malaria incidence rates also fell by 37% between 2000 and 2015.

Childhood mortality due to malaria fell by 65% worldwide and by 71% in Africa. This is particularly impressive and an important win since children under five years of age are highly susceptible to malaria infection and death.

In 2015, the global burden of malaria is highly concentrated in 17 countries, mostly in Africa and progress in reducing malaria incidence in these high burden countries has lagged behind other countries.
These data thus far are dramatic and encouraging but given the many challenges including poorly functioning health systems, climate change and global economy, a coordinated, multi-pronged global response with continued investment is needed. The Global Technical Strategy for Malaria was approved by the WHO in 2015. This strategy follows the timeline of the sustainable development goals and aims to reduce both malaria incidence and mortality by 90%. The framework provided in the technical strategy consists of 3 pillars, that could be used as a foundation for anti-malaria strategies and programs. The three pillars are a) ensure universal access to malaria prevention, diagnosis and treatment; b) accelerate efforts towards elimination and attainment of malaria-free status; and c) transform malaria surveillance into a core intervention. The framework aims to provide clear defined paths to achieve the lofty goals of malaria reduction and elimination.

Now is the time for consistent financial support from national governments and other donors to keep the momentum going in our fight against malaria. Together we can end malaria!

Plasmodium goes viral as the global health community observes World Malaria Day

If you think you’re too small to accomplish something big, picture yourself locked in a room with a mosquito. –African proverb  

An African woman lies under a light-blue bed net.
Mali 2010 @ Barbara Sigge/MSF

Yesterday, World Malaria Day was observed by organizations and communities all over the world with all the resolve appropriate for one of the world’s deadliest diseases.  According to the WHO, approximately half of the world is at risk for the disease.  Though most of the cases and deaths occur in sub-Saharan Africa, malaria was present in 108 countries and territories in 2008, causing approximately 247 million cases and nearly one million deaths.1  Most deaths are in children under 5.  The international day of observation was recognized by high-profile celebrities, NGOs, and small communities in a variety of ways.  But the newest – and potentially the most effective – way to raise both money and awareness is by going viral with the protozoan parasite.  

Malaria first went viral when Ashton Kutcher celebrated his beating CNN to one million followers on Twitter by donating $100,000 to Malaria No More to purchase 10,000 mosquito nets.2  Through his donation, 89,724 insecticide-treated bed nets were sent to villages in Senegal.  By using the RT2Give Twitpay service, any Twitter user can retweet a message from their malaria-related non-profit of choice and donate $10 to Malaria No More.  Internet Explorer and Firefox users can also download and use the Nothing But Nets browser toolbar, which raises money every time it’s used to search and shop online.  

The battle against malaria continues to rage on many fronts, and much progress has been made.  A variety of rapid diagnostic tests are available to facilitate accurate diagnosis and prompt treatment, requiring only a drop of blood and giving results in 15 minutes.  Artemisinin-based combination therapy acts quickly with few side effects and has proven extremely effective at treating malaria cases.3  Malaria vaccine candidates, though they only confer partial protection, have shown great promise and are currently in Phase III testing.4  However, there is still much work to be done: insecticide-treated bed nets must be made more widely available, reliable testing and treatment need to be implemented on a much wider scale, and care and treatment must be made more affordable and accessible.   

When UN Secretary General Ban Ki-moon announced the first World Malaria Day in 2008, he made the bold proposal of ending malaria deaths by the end of 2010 by ensuring universal coverage in Africa.  In an op-ed piece in the Guardian, he cautioned that while we may not be able to wipe out malaria right away, we can combat it effectively if we act together.  “We have the resources and the know-how. But we have less than 1,000 days before the end of 2010. So let’s get to work.”5 

~~~traduction française~~~ Continue reading “Plasmodium goes viral as the global health community observes World Malaria Day”

Kala-azar and the Mark of the Jungle

Blog contributor: Jessica M. Keralis

In Peru, a nose that has been flattened and pushed into the face – the characteristic disfigurement caused by leishmaniasis – is referred to as “the mark of the jungle.”  In addition to the damaged self-image it causes in people with leishmaniasis, the “mark” comes with a stigma that leads to ridicule from others, shame, and sometimes even being driven from their own communities.­1

Leishmaniasis is caused by a protozoan parasite of the genus Leishmania.  Humans are infected through a bite from an infected female phlebotomine sand fly and can develop one of three main types of the disease.  Cutaneous leishmaniasis, by far the most common form, causes lesions on the skin; there are approximately 1.5 million cases worldwide each year.2 Mucocutaneous leishmaniasis destroys the mucous membranes of the nose, mouth, and throat and often leads to pronounced disfigurement.3 Visceral leishmaniasis is the most severe, which is characterized by fever, weight loss, anemia, and enlargement of the spleen and liver.  This disease, called kala-azar (meaning “black fever”) on the Indian sub-continent, occurs in 500,000 people each year and causes approximately 50,000 deaths.4 Leishmaniasis is present in 88 countries, 72 of which are developing countries, on four continents.5 The spread of HIV has compounded the problem: in cases of co-infection, the leishmaniasis parasite accelerates the onset of AIDS by suppressing the immune system and stimulating virus production.  Cases of co-infection have been reported in 38 countries on all four continents where the disease is endemic. 6 Unfortunately, the disease is very under-reported: only 32 affected countries require reporting.

The disease burden is exacerbated by the social stigma in response to the effects of the parasite.  Many affected are ostracized from their communities because of their disfigurements.  In Pakistan and Afghanistan, cutaneous leishmaniasis is called Kal Dana (“the year-long sore”).  Affected children are isolated, women are considered unsuitable for marriage and mothers are separated from their children.7 The problem is particularly bad in Nepal, where the caste system prevents “untouchables” from being treated. 1 Ultimately, poverty and ignorance are at the root of leishmaniasis.  It is poverty that drives people in Peru into the jungle to cut lumber or pan for gold, to sleep without bednets, and to delay treatment so they can earn for their families. 1 Dr Robert Killick-Kendrick, a leading parasitologist, recently said in an interview with the WHO that while progress in controlling leishmaniasis is slow, there have been encouraging recent developments. 4 He lists five key factors that are important in controlling all vector borne diseases: peace, long-term political commitment, finance, sound control methods likely to succeed, and public health education.  “It’s easy to sit in our armchairs and list the problems for the control of VL – or any other vector-borne disease,” he says. “But I am optimistic: with adequate funding, long-term political support and energy coupled with a little imagination, it must be possible to tame this disease, if not get rid of it altogether.”