Posts Tagged 'vaccines'

Vaccinating the Haitian Cholera…

Haiti struggles through many things — earthquakes, hurricanes, and disease. Cholera, first and foremost, seemingly brought to the country by the very people trying to help it. The UN aid workers were pinpointed as the source of the outbreak.

There is much talk of vaccinating for cholera in Haiti. Many believed it wouldn’t work and to get the coverage needed for it to be effective was virtually impossible given the nature of poverty within the population. The reasons were numerous and voiced. In April of last year, vaccinations finally started, and it has seemed to be somewhat successful.

New research, published in Nature’s Scientific Reports, adds more wait to the usefulness of a vaccination campaign for cholera in Haiti.

“You don’t have to immunize everybody. Even if we could get an immunization rate in the range of 40 to 50 percent, it should be possible to control recurrent cholera outbreaks,” Dr Morris of the Emerging Pathogens Institute in Florida, said in a press release. “That should be enough to tilt things in your favor so that you can start getting control of the disease in these areas, to where, hopefully, rates of transmission will slow and numbers of cases will gradually die off.”

Haiti’s population was immunologically naïve to cholera after its long absence, so the potential for a severe cholera epidemic was high, and there was the fear that the outbreak would establish a long-term endemicity, marked by the traditional recurrent seasonal epidemics.

The paper ends by mentioning the obvious caveat of them all; “However, to achieve optimal protection of the population, vaccination would need to be combined with other measures that permanently improve water systems and/or otherwise decrease the risk of transmission from environmental sources.”

A short history of Leishmania vaccines…

In February of this year we saw the launch of the first human trial for a new vaccine for Visceral Leishmaniasis.

The new trial was launched by the Infectious Disease Research Institute (IDRI) in Washington, USA with the plan to hold a further Phase 1 trial in India. The Bill & Melinda Gates Foundation is funding the Phase 1 clinical trials, as part of the recently announced worldwide partnership with the WHO and 13 pharmaceutical companies to control or eliminate 10 neglected tropical diseases.

This new development on a Leishmania vaccine can be added to a fast-expanding list of so-called “anti-poverty” vaccines; the famed RTS,S malaria vaccine that last year proved to be effective (albeit not to levels some would deem completely effective), rabies, hookworm, Schistosomiasis, and a dengue vaccine to be seen before 2015.

Visceral Leishmaniasis represents one form of a disease seen across much of the old and new world — across 88 countries — and is one of the most common parasitic infections behind malaria. In India, they refer to it after the Hindi word that means black fever — kala-azar. The black fever that haunts those infected and whose skin becomes dark and gray. Where ever it infects, kala-azar is the most deadly form of leishmaniasis.

For the sake of brevity, the history of a Leishmaniasis vaccine dates back to the 1940s with “leishmanization” as it was known. The deliberate inoculation of infective and virulent Leishmania from the “exudate” of a lesion on the skin. Crude, unreproducible and wholly unsafe, the method of leishmanization gave way to first generation vaccines, consisting of killed or live attenuated parasites.

Second generation vaccines came much later; when we were able to genetically modify the leishmania species themselves or use bacteria or viruses as surrogates carrying leishmania genes.

Some methods rely on the identification, thanks to genome sequencing, of proteins on the parasite’s surface that can be used to elicit an immunological response. And most importantly, a protein that is expressed in more than one life cycle stage of the parasite.

More recently, the ability to manipulate the Leishmania genome to create genetically modified parasites by introducing or eliminating genes meant the potential of using live attenuated parasite vaccine. And represents a powerful alternative for developing a new generation vaccine against leishmaniasis.

The prospect of DNA vaccines came only when it was discovered that directly injecting relatively small circles of DNA that encode foreign proteins could lead to a specific immune response. Only then was a new perspective of vaccine formation imagined. One that had no need for the invading parasite itself, and one driven by our advances in molecular biology and biotechnology.

Elliciting an immune response to leishmania is something easier said than done. Many early vaccines that showed promise lacked the ability to ellicit the exact kind of immune response. This is a fact made even more complicated by the fact that leishmania as aparasite lives within immune system cells (macrophages). Leishmania survive within host cells, hiding and inhibiting the cell’s interior defenses.

The IDRI vaccine, known as LEISH–F3 + GLA-SE, is a highly purified, recombinant vaccine. It incorporates two fused Leishmania parasite proteins and a powerful adjuvant to stimulate an immune response against the parasite.

With a slow realisation that the geographical range for leishmaniasis is expanding, a vaccine could not come at a better time. Spurred on by global warming, mass migration and rapid urbanization, cases are being reported in previously unaffected areas.

Vaccines are seen as the silver bullet — the game changer. Sophisticated pieces of science that are so simple in their function. For all we know about the way our own immune system works, there still lies large blind spots and gaps in our knowledge. The delicate balance and complexity hidden within the immune system is only made evident when diseases and germs find a way to avoid and exploit it. The possibility of a kala-azar vaccine is made even more sweeter by the simple fact that the leishmaniases are unique among parasitic diseases because a single vaccine could have the potential to protect against other leishmania diseases.

Image — source.

Originally appearing at

Dunning, N. (2009). Leishmania vaccines: from leishmanization to the era of DNA technology Bioscience Horizons, 2 (1), 73-82 DOI: 10.1093/biohorizons/hzp004

Chakravarty, J., Kumar, S., Trivedi, S., Rai, V., Singh, A., Ashman, J., Laughlin, E., Coler, R., Kahn, S., Beckmann, A., Cowgill, K., Reed, S., Sundar, S., & Piazza, F. (2011). A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine for use in the prevention of visceral leishmaniasis Vaccine, 29 (19), 3531-3537 DOI: 10.1016/j.vaccine.2011.02.096

Nagill, R., & Kaur, S. (2011). Vaccine candidates for leishmaniasis: A review International Immunopharmacology, 11 (10), 1464-1488 DOI: 10.1016/j.intimp.2011.05.008

The Opposite of Patient Zero…

Ali Maow Maalin.

On October 26, 1977, Ali Maow Maalin from Somalia, was the last person known to have contracted smallpox (naturally). He was 23 at the time and unvaccinated. He eventually recovered.

How the malaria vaccine works…

March 2009 — 15,460 children are enrolled in a unique vaccine study. The study, encompassing seven African countries, was the first of its kind to test the efficacy of a vaccine against a parasitic-borne disease. That in itself was something many thought would never be seen.

Yesterday — October 18th — the results of that study, the largest ever malaria study, was published in the New England Journal of Medicine, spelling out new hope for fighting a disease that accounts for 800,000 lives lost on a yearly basis – most of them children under the age of 5.

The vaccine, that has been in development for the better part of two decades — the interestingly titled RTS,S – provided protection against both clinical and severe malaria in African children. RTS,S was designed as a vaccine to prevent malaria infection, but it has proven to prevent clinical and severe disease. The trial was a randomized, controlled, and doubleblind designed to evaluate vaccine efficacy, safety, reactogenicity, and immunogenicity in children up to 32 months after the administration of the first dose.

From the abstract:

“In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64).”

It should be stressed that no one is viewing this new vaccine as the miracle drug or the silver bullet for this disease. Far from it. Researchers are right to point out “A malaria vaccine, deployed in combination with current malaria-control tools, could play an important role in future control and eventual elimination of malaria in Africa”.

Just another weapon in the armoury in the fight against the disease. Indeed, none of the malaria vaccines in various stages of the development process have shown anywhere near 100% efficacy.

RTS,S is the most advanced vaccine candidate against malaria to date, and the story of RTS,S is not just a story of how much we know and understand disease, but also how much we don’t know. The landmarks and feats that went in to getting a workable vaccine for malaria is one done in spite of the gaps in our knowledge. The questions left unanswered offer an important starting point and challenge in the quest to understand the protection afforded by RTS,S and to build a more efficacious second generation vaccine against malaria.

The malaria parasite has a complex life cycle. One that is needed to be understood to understand the vaccine.The life cycle of the malaria parasite starts with the bite of an infected mosquito (female anopholese), inoculating sporozoites into the human host. Within the host it is complex, consisting of  an asymptomatic liver stage (pre-erythrocytic) infection followed by a symptomatic blood stage (erythrocytic) infection. Sporozoites infect liver cells and mature into schizonts. The liver cell ruptures releasing merozoites, which infect red blood cells.

The parasite’s life cycle within the liver is very short. At one point it was thought that a vaccine against the liver stage would prove too ineffective, as immune responses induced by vaccination against liver stage parasites could not act quickly enough to destroy the infected liver cells (hepatocytes) and to prevent the release of liver-stage parasites (merozoites) into the blood.

“During its remarkable journey from conception and design in the early 1980s to the multicenter Phase 3 trial currently underway across sub-Saharan Africa, RTS,S has overcome tremendous challenges and disproved established vaccine paradigms.”

For the sake of brevity, the story of a malaria vaccine begins its life in the 1960s. Researchers at New York University demonstrated that immunization of animals with the bites of irradiated-attenuated infected mosquitoes could protect against infectious sporozoites (the form of the parasite the mosquito injects when it bites). It was this demonstration that led to the identification of the Plasmodium falciparum circumsporozoite (CS) protein expressed on sporozoites  and liver stage schizonts – the basis of the RTS,S vaccine we have today.

The CS protein is present in large amounts on the surface of sporozoites and is also expressed by liver schizonts. The modestly sized CS protein is one involved in sporozoite invasion of mosquito salivary glands as well as in binding to hepatocytes prior to invasion of the liver cells.

The pertinent question is how the vaccine confers immunity, given the very small window of opportunity in which the parasite is exposed.

“immunity conferred by the RTS,S vaccine could act by attacking sporozoites during the short time in which they are in the circulation, disabling them and preventing them from invading liver cells, or by attacking liver schizonts.”

The short answer is we don’t really know. The even shorter answer is that we may never really know, as identification of an immunological measurement that provides a reliable measure of clinical protection in RTS-vaccinated individuals from all populations might never be possible.

RTS,S candidate malaria vaccines induce very high titres of anti-circumsporozoite antibodies as well as a strong CD4 T-cell response (characterised by the production of inflammatory cytokines such as interferon γ), which could contribute to the killing of the liver schizonts.

The chemistry of the vaccine itself is more concrete. The vaccine antigen consists of 19 copies of the central tandem repeats and C-terminal region of the CS protein fused to hepatitis B surface antigen (HBsAg), and co-expressed with unfused HBsAg in Saccharomyces cerevisiae cells.

In order to prevent allergic reactions and autoimmunity, the immune system is generally tolerant to antigens, unless antigens trigger “danger signals” that mobilize the immune system to react aggressively. This is the basis of adjuvant systems. Adjuvants have been long known for their ability to trigger danger signals and have been widely used for immunization purposes. The RTS,S adjuvant comes in two flavours (out of 11 possible different formulations tested) — AS02 and AS01.

The general requirement for an adjuvant formulation (among others) is to stabilize antigen and slow its release to the immune system. AS02 is a squalene-in-water emulsion containing MPL (monophosphoril lipid A), and a saponin (triterpene glycoside) derived from the bark of the plant Quillaja saponaria (QS21). QS21 is thought to function to trap components of the vaccine formulation through hydrophobic interactions and thereby slows their release to the immune system. MPL is a derivative of a lipopolysaccharide that triggers danger signals in macrophages and dendritic cells, and promotes secretion of pro-inflammatory cytokines.

AS01b was developed to increase immunogenicity, in which the oil-in-water emulsion of AS02 was replaced by liposomes. The liposomes replacement meant that RTS,S is delivered to the trans-Golgi in antigen-presenting cells, where the RTS,S is efficiently processed and enhances MHC class I and class II antigen presentation to T cells.

The protection conferred by RTS,S vaccine does not seem to be strain specific. A valid concern is that there is a possibility that RTS,S vaccination could lead to the emergence of a P. falciparum parasite strains carrying polymorphisms in the CS protein. However, some recent trials have shown no increase in the frequency of genetically variant parasites in vaccinated groups.

All in all the RTS,S vaccine is the spark of promise and hope in controlling a disease that causes so much human death and suffering. But it is by no means that last word. As it’s often said, the miracle drug will always be a hard pill to swallow. In the case of diseases of the world’s poorest, there is the problem that the miracle drug will always be one too expensive. More funding will be needed to understand more about this vaccine’s efficacy, the duration of protection, and how best to implement this vaccine to most effectively to control malaria.

The RTS,S malaria vaccine
First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children
Immunological correlates of protection for the RTS,S candidate malaria vaccine

What had I twaught…

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