GlaxoSmithKline Seeks to Market RTS,S Malaria Vaccine

by

British drugmaker GlaxoSmithKline is seeking approval to market the world’s first malaria vaccine, after trials showed that it significantly cut cases of the disease in children.

Results from latest clinical trial of the RTS,S vaccine were unveiled at a conference in Durban, South Africa on Tuesday.

It showed that after 18 months of follow-up, the vaccine halved the number of malaria cases in young children and reduced the number of cases in infants by about 25 percent.

The trials were conducted on 15,000 infants and young children in seven African countries.

The drugmaker said in a statement that it plans to submit an application for the vaccine to the European Medicines Agency (EMA). It said that the World Health Organization may recommend use of the vaccine starting in 2015, if the EMA gives the vaccine a positive scientific opinion.

The RTS,S vaccine is being developed along with the non-profit PATH Malaria Vaccine Initiative, with grant funding from the Bill & Melinda Gates Foundation.

GSK says that once approved the vaccine will be priced at the manufacturing cost plus a margin of five percent that would be reinvested for research into future malaria vaccines.

The World Health Organization reports that malaria kills up to 800,000 people a year, with most deaths occurring among children in Africa.

Source: VOA

Phase III Trial of RTS,S Malaria Candidate Vaccine Reduces Malaria by One Third

by

Results from a pivotal, large-scale Phase III trial, published online today in the New England Journal of Medicine, show that the RTS,S malaria vaccine candidate can help protect African infants against malaria. When compared to immunization with a control vaccine, infants (aged 6-12 weeks at first vaccination) vaccinated with RTS,S had one-third fewer episodes of both clinical and severe malaria and had similar reactions to the injection. In this trial, RTS,S demonstrated an acceptable safety and tolerability profile.

Eleven African research centres in seven African countries1 are conducting this trial, together with GlaxoSmithKline (GSK) and the PATH Malaria Vaccine Initiative (MVI), with grant funding from the Bill & Melinda Gates Foundation to MVI.

Dr. Salim Abdulla, a principal investigator for the trial from the Ifakara Health Institute, Tanzania, said: “We’ve made significant progress in recent years in our battle against malaria, but the disease still kills 655,000 people a year—mainly children under five in sub-Saharan Africa. An effective malaria vaccine would be a welcome addition to our tool kit, and we’ve been working toward this goal with this RTS,S trial. This study indicates that RTS,S can help to protect young babies against malaria. Importantly, we observed that it provided this protection in addition to the widespread use of bed nets by the trial participants.”

Efficacy
When administered along with standard childhood vaccines,2 the efficacy of RTS,S in infants aged 6 to 12 weeks (at first vaccination) against clinical and severe malaria was 31% and 37%,3 respectively, over 12 months of follow-up after the third vaccine dose.4 Insecticide-treated bed nets were used by 86% of the trial participants, which demonstrated that RTS,S provided protection beyond existing malaria control interventions. The efficacy observed with RTS,S last year in children aged 5-17 months of age against clinical and severe malaria was 56% and 47%, respectively. Follow-up in this Phase III trial will continue and is expected to provide more data for analyses to better understand the different findings between the age categories.

Dr. Abdulla added: “The efficacy is lower than what we saw last year with the older 5-17 month age category, which surprised some of us scientists at the African trial sites. It makes us even more eager to gather and analyze more data from the trial to determine what factors might influence efficacy against malaria and to better understand the potential of RTS,S in our battle against this devastating disease. We were also glad to see that the study indicated that RTS,S could be administered to young infants along with standard childhood vaccines and that side effects were similar to what we would see with those vaccines.”

Safety
There was no increase in overall reporting of serious adverse events5 (SAEs) between the infants vaccinated with the RTS,S malaria vaccine candidate and infants in the control group, which received a comparator vaccine. Side effects primarily included local injection site reactions, which were less frequent following RTS,S vaccinations compared to the DTP-HepB/Hib vaccine. Fever was reported more frequently following RTS,S vaccinations than the control vaccine group (30.6% versus 21.1% of vaccine doses, respectively).

Two new cases of meningitis were reported in the 6-12 week-old infant age category in addition to the 9 reported last year; one in the RTS,S group and one in the control vaccine group. Further analysis revealed a bacterial cause of the meningitis in 7 of the 11 cases.

Sir Andrew Witty, CEO, GSK said: “While the efficacy seen is lower than last year, we believe these results confirm that RTS,S can help provide African babies and young children with meaningful protection against malaria. They take us another important step forward on the journey towards having a new intervention available against this disease, which is a huge burden on the health and economic growth of Africa. We remain convinced that RTS,S has a role to play in tackling malaria and we will continue to work with our partners and other stakeholders to better understand the data and to define how the vaccine could best be used to provide public health benefit to children in malaria endemic areas in Africa.”

David Kaslow, Director of the PATH Malaria Vaccine Initiative, said: “Determining the role of RTS,S in Africa will depend on analyses of additional data. We are now an important step closer to that day. Success in developing malaria vaccines depends on many factors: at the top of the list are partnerships and robust evidence, coupled with an understanding that different combinations of tools to fight malaria will be appropriate in different settings in malaria-endemic countries. My congratulations go out to the team at GSK and to the African research centres for their exemplary conduct of this trial.”

“This is an important scientific milestone and needs more study,” said Bill Gates, co-founder of the Bill & Melinda Gates Foundation. “The efficacy came back lower than we had hoped, but developing a vaccine against a parasite is a very hard thing to do. The trial is continuing and we look forward to getting more data to help determine whether and how to deploy this vaccine.”

The vaccine is being developed in partnership by GSK and MVI, together with prominent African research centres1*. The collaborators are represented on the Clinical Trials Partnership Committee, which oversees the conduct of the trial. An extended team of organisations work on RTS,S, including scientists from across Africa, Europe, and North America. Major funding for clinical development of RTS,S comes from a grant by the Bill & Melinda Gates Foundation to MVI.

Looking ahead
Follow-up in this Phase III trial will continue to provide more data for analyses to better understand the different findings between the age categories. These data and analyses should also provide insights into the vaccine candidate’s efficacy in different malaria parasite transmission settings. More data on the longer-term efficacy of the vaccine during 30 months of follow-up after the third dose, and the impact of a booster dose are expected to be publicly available at the end of 2014.

The data and analyses will inform the regulatory submission strategy and, if the required regulatory approvals are obtained and public health information, including safety and efficacy data from the Phase III programme, is deemed satisfactory, the World Health Organization (WHO) has indicated that a policy recommendation for the RTS,S malaria vaccine candidate is possible as early as 2015, paving the way for decisions by African nations regarding large-scale implementation of the vaccine through their national immunisation programmes. An effective vaccine for use alongside other measures such as bed nets and anti-malarial medicines would represent a decisive advance in malaria control.

GSK and MVI are committed to making this vaccine available to those who need it most, should it be approved and recommended for use. In January 2010, GSK announced that the eventual price of RTS,S (also known as MosquirixTM) will cover the cost of manufacturing the vaccine together with a small return of around 5% that will be reinvested in research and development for second-generation malaria vaccines or vaccines against other neglected tropical diseases.

About RTS,S
RTS,S is a scientific name given to this malaria vaccine candidate6 and represents the composition of this vaccine candidate. RTS,S aims to trigger the immune system to defend against Plasmodium falciparum malaria parasite when it first enters the human host’s bloodstream and/or when the parasite infects liver cells. It is designed to prevent the parasite from infecting, maturing, and multiplying in the liver, after which time the parasite would re-enter the bloodstream and infect red blood cells, leading to disease symptoms. In the Phase III efficacy trial, RTS,S is administered in three doses, one month apart. A booster dose administered 18 months after the third dose is also being studied in the trial.

The vaccine, based on a protein first identified in the laboratory of Drs Ruth and Victor Nussenzweig at New York University, was invented, developed, and manufactured in laboratories at GSK Vaccines in Belgium in the late 1980s and initially tested in US volunteers as part of a collaboration with the US Walter Reed Army Institute of Research.

In 2001, the MVI entered into partnership with GSK to study the vaccine candidate’s ability to protect young children in sub-Saharan Africa. Over time, the partnership expanded to include the 11 African research centres and, in some instances, associated scientific institutions from Europe and the United States.

With more than US$200 million in grant monies from the Bill & Melinda Gates Foundation, MVI contributes financial, scientific, managerial, and field expertise to the development of RTS,S. GSK takes the lead in the overall development of RTS,S and has invested more than $300 million to date and expects to invest more than $200 million before the completion of the project.

About the study
The first complete set of results in children aged 5 to 17 months and combined data for severe malaria in the first 250 cases from those aged 6 weeks to 17 months were published in the New England Journal of Medicine in November 2011. The Phase III trial has been designed in consultation with the appropriate regulatory authorities and the WHO. It is conducted in accordance with the highest international standards for safety, ethics, and clinical practices and is overseen by an independent data safety monitoring committee.

About GSK Vaccines
GlaxoSmithKline Vaccines is active in vaccine research and development. Headquartered in Belgium, GSK Vaccines has 14 manufacturing sites strategically positioned around the globe. Of the 1.1 billion doses of our vaccines we distributed in 2011, over 80% went to developing countries, which include the least developed, low- and middle-income countries.

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information, please visit www.gsk.com.

The PATH Malaria Vaccine Initiative (MVI) is a global program established at PATH through an initial grant from the Bill & Melinda Gates Foundation. MVI’s mission is to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world. MVI’s vision is a world free from malaria. For more information, please visit www.malariavaccine.org.

PATH is an international nonprofit organization that transforms global health through innovation. PATH takes an entrepreneurial approach to developing and delivering high-impact, low-cost solutions, from lifesaving vaccines and devices to collaborative programs with communities. Through its work in more than 70 countries, PATH and its partners empower people to achieve their full potential. For more information, please visit www.path.org.

1  Burkina Faso – Nanoro, Institut de Recherche en Science de la Santé (IRSS) / Centre Muraz
Gabon – Lambaréné Albert Schweitzer Hospital, Medical Research Unit
Ghana – Agogo/Kumasi: School of Medical Sciences, Kwame Nkrumah University of Science and Technology; Kumasi Centre for Collaborative Research, Agogo Presbyterian Hospital
Ghana – Kintampo: Kintampo Health Research Centre, Ghana Health Service
Kenya – Kilifi, KEMRI-Wellcome Trust Research Program
Kenya – Kombewa (Kisumu), KEMRI-Walter Reed Project Kenya Medical Research Institute
Kenya – Siaya (Kisumu), KEMRI-CDC Research and Public Health Collaboration
Malawi – Lilongwe, University of North Carolina Project at the Tidziwe Centre
Mozambique – Manhica, Centro de Investigação em Saúde de Manhiça
Tanzania – Bagamoyo, Ifakara Health Institute
Tanzania – Korogwe, National Institute for Medical Research, Tanzania, Kilimanjaro Christian Medical Centre
2  Standard childhood vaccines used were the combined diphtheria-tetanus-whole-cell-pertussis, hepatitis B, and Haemophilus influenzae type b vaccine (DTPwHepB/Hib) and the oral polio virus vaccine (OPV).
3  Based on According To Protocol (ATP) statistical methodology.
4 Average risk for malaria in the control group was 0.9 clinical episodes per child per year and 2.3% of the children experienced at least one episode of severe malaria.
5  A serious adverse event refers to any medical event that occurs during the course of a clinical trial and that results in death, is life threatening, requires inpatient hospitalization, or results in a persistent or significant disability or incapacity needs, regardless of whether the event is considered by the investigator to be caused by the study vaccination. All SAEs are reported to regulatory authorities.
6  Contains QS-21 Stimulon® adjuvant licensed from Antigenics Inc, a wholly owned subsidiary of Agenus Inc. (NASDAQ: AGEN), MPL and liposomes

Source: Malaria Vaccine Initiative. Reproduced from the Malaria Vaccine Initiative website at www.malariavaccine.org, Nov. 9, 2012

GlaxoSmithKline Malaria Vaccine Candidate Results Disappointing

by

The latest clinical trial of the world’s leading malaria vaccine candidate produced disappointing results on Friday. The infants it was given to had only about a third fewer infections than a control group. Three shots of the vaccine, known as RTS, S or Mosquirix and produced by GlaxoSmithKline, gave babies fewer than 12 weeks old 31 percent protection against detectable malaria and 37 percent protection against severe malaria, according to an announcement by the company at a vaccines conference in Cape Town.

Read more, via The New York Times.

Malaria Prophylaxis – Delaware

by

QUESTION

Where can I get vaccinated for malaria in Wilmington, DE?

ANSWER

Currently there is no vaccine for preventing malaria.  However, there are a number of ways to prevent malaria. These can be placed into two categories: medication and vector protection.

For medication, there are drugs you can take to prevent the malaria parasite from developing after being bitten by an infected mosquito. These drugs are known as “chemoprophylaxis.” There are several different kinds, such as doxycycline, mefloquine (marketed as Lariam), atovaquone-proguanil (marketed as Malarone) and chloroquine—the type you use depends on the type of malaria present in the area. For example, in much of Africa and India, malaria is resistant to chloroquine, so this cannot be used as a prophylactic. In parts of Thailand, resistance to mefloquine has emerged. However, if the appropriate type of prophylaxis is used, it is very effective against malaria.

Vector prevention involves protecting oneself against getting bitten by mosquitoes. This can involve wearing long-sleeved clothing in the evenings and at night, when malaria mosquitoes are most active, or wearing insect repellent on exposed skin. Indoor residual spraying, whereby repellent and insecticides are sprayed inside the house, can also be used to bring down the number of mosquitoes.  Another very effective technique for preventing malaria is to sleep under a long-lasting insecticide-treated bednet. The mesh acts as a barrier against the mosquitoes, and the insecticide impregnated in the mesh further repels the mosquitoes and prevents them from biting through the mesh.

Check the “Malaria Overview” section of malaria.com for a map showing where malaria is found, and for appropriate  preventive treatment. You can also look at the CDC website and consult your physician before traveling.

First in Malaria: U.S. or China?

by

QUESTION

Who discovered the world’s first malaria vaccine? Is it the US marines in Washington DC or the People’s Republic of China?

ANSWER

Unfortunately there is still no effective malaria vaccine.  You might be referring to the race between the US and China to find an effective malarial treatment during the Vietnam War years.  Currently, artemisinins, from the wormwood plant, discovered in China is the recommended treatment for malaria caused by Plasmodium falciparam.

Malaria Vaccine

by

QUESTION

For how long does this vaccine work?

ANSWER

There is not yet a commercially available vaccine against malaria. Recently, results were published (in the New England Journal of Medicine – press releases and news reports about the study are available through the main page of www.malaria.com) presenting preliminary findings of the first Phase 3 clinical trial for a vaccine, called RTS,S. The trial will not fully conclude until 2014, and so we won’t know for a few more years exactly how effective it is or for how long. The results that were just published showed only a 50% level of protection against malaria from the vaccine (in African children, most of whom also slept under bednets and generally had access to a high standard of medical care), and that value appeared to decrease over time, with protection levels after a year only about 35%. However, these early findings are still potentially promising, especially for remote areas with low access to other more immediate health care options.

The “E” word and the “V” word: Two Holy Grails of Malaria Control

by

The Roll Back Malaria Partnership talks confidently of elimination—many others question if this is possible without new interventions. The recent publication of the first Phase 3 clinical trial for a malaria vaccine shows promise, but is it actually good enough?

REVIEW OF:

  • Roll Back Malaria Partnership, “Eliminating Malaria: Learning from the Past, Looking Ahead”, Progress & Impact Series, vol 8, October 17th, 2011
  • RTS,S Clinical Trials Partnership, “First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children”, New England Journal of Medicine, October 18th, 2011

This past week has been a busy one in the world of malaria research and control. On Monday, the Roll Back Malaria Partnership (a joint enterprise between the World Health Organisation, UNICEF, UNDP and the World Bank) released the 8th volume in its Progress & Impact Series, entitled, “Eliminating Malaria: Learning from the Past, Looking Ahead”. The report summarizes RBM’s malaria eradication and elimination efforts to date, and outlines action plans and on-going progress in all malaria-endemic countries around the world. The overall tone of the document is highly positive, emphasizing the various success stories of countries achieving or nearing elimination of malaria in different parts of the world.

This is nowhere more obvious than in Chapter V’s regional summary of the WHO African Region, where no mention is made of the countries that are struggling the most with malaria control, but instead the focus is entirely on congratulating the 4 countries that have already achieved elimination, and praising those 12 countries with existing or imminent plans to move towards elimination. The document as a whole is a comprehensive overview of the status of malaria control, although somewhat light on epidemiological specifics. I was also dismayed to see at least two large photographs of fingerprick blood samples being taken without protective gloves being worn, against all standard diagnostic protocol!

But that’s an aside. In their conclusion, the authors primarily support “existing interventions”, and caution against waiting for “better options” to become available, given the measurable successes already being achieved in many settings using already-available control strategies such as bednet distribution, improved access to diagnosis and treatment and vector control.

It is not perhaps without a touch of irony then that on Tuesday, the first comprehensive analysis of an on-going Phase 3 clinical trial for one of the most promising malaria vaccine candidates was published, in the New England Journal of Medicine. The quest for a malaria vaccine has been protracted, expensive and, thus far, basically unsuccessful, yet to many, global elimination of malaria will not succeed without an intervention that gives lasting protection against re-infection, given the extraordinarily high rates of transmission of malaria in some parts of the world.

The paper reports a reduction of clinical malaria and severe malaria by 56% and 47% respectively, although protection seemed to decay over time; further evaluations will be analysed in 2012 and at the conclusion of the trial in 2014. The authors of the paper are careful to note that the trial was conducted in a cohort with generally good access to medical care, well-supplied health facilities and widespread usage of bednets and other control interventions. As such, mortality from malaria was low even in the control group, and so conclusions about the impact of the vaccine on malaria-related deaths may be difficult to draw.

Moreover, the paper did not directly analyse the relationship between the antibody titers (levels of immune protection to malaria in the blood) conferred by the vaccine and if the patient got malaria or not. In previous studies (for example, Bejon et al.’s 2008 paper also in the NEJM), this relationship was weak, suggesting that the vaccine itself was not contributing strongly to levels of protection against infection, and that other factors were at play. One suggestion is that the adjuvant, a non-specific immune-response enhancer included in the vaccine, may itself play a role, and given that the control groups received vaccines with a different adjuvant, this may partially account for the variations in malaria prevalence seen between the children studied. However, these early data still show potential at least for reducing clinical cases of malaria in a highly-endemic African setting.

It should be noted that these findings do not come entirely as a surprise; there were early signs of potential, at least partial, protection from this vaccine (the results of the Phase 2b trials were published in The Lancet back in 2004). Despite this, the word “vaccine” is mentioned but twice in the latest RBM report. I have a deep admiration for the RBM and all that the partnership has achieved thus far in the struggle to control malaria throughout the world. Without a doubt, the scale of the problem is immense, and they are right to emphasise the enormous achievements many countries have realized, and particularly in reducing malaria mortality in the last 10 years. Nor would I advocate for countries to latch onto the promise of a vaccine too quickly; clearly more research is needed to evaluate the long-term efficacy of the vaccine, as well as its impacts specifically on mortality as opposed to morbidity; hopefully we will have some of these answers in a year, at the conclusion of the Phase 3 trial.

However, in the meantime, there is clearly a huge opportunity for using these preliminary findings to determine what role there might be, if any, for the vaccine in its existing form as part of new and improved control strategies. For example, if the vaccine is not fully protective, might it, perhaps counter-intuitively, actually be more effective in areas which are already well on their way to successful control, by reducing transmission below that which is viable for the persistence of malaria? Or will its role in reducing incidence of severe disease be equally well utilized in extremely high prevalence and low health infrastructure areas, where access to diagnosis and treatment is the limiting step in effecting control? To its credit, RBM has acknowledged this since the publication of the vaccine trial results, with the following statement from the CDC: “These promising vaccine trial results add to the hope that adding an effective vaccine to current malaria interventions will move us closer to that goal.” Perhaps the “better option” wasn’t so long in coming after all.

 

Glaxo’s RTS,S Malaria Vaccine Shows Promise

by

Preliminary results from the trial of a malaria vaccine show that it protected nearly half of the children who received it from bouts of serious malaria, scientists said Tuesday. The vaccine, known as RTS,S and made by GlaxoSmithKline, has been in development for more than 25 years, initially for the American military and now with most of its support from the Bill and Melinda Gates Foundation. [Read more…]

RTS,S Malaria Vaccine

by

QUESTION:

What information can you provide on this vaccine candidate?

ANSWER:

RTS,S is a vaccine candidate against Plasmodium falciparum malaria which works by encouraging the host’s body to produce antibodies and T cells which diminish the malaria parasite’s ability to survive and reproduce in the liver.

Produced by GlaxoSmithKline, RTS,S is the first vaccine candidate against Plasmodium falciparum that has reached advanced (Phase III) clinical field trials on a large scale. It was developed way back in 1987, and had successive trials in the United States in 1992 and then in Africa in 1998. In 2001, GSK and the Malaria Vaccine Initiative at PATH went into a public-private partnership, with grant money from the Bill and Melinda Gates Foundation, to develop the vaccine for use in children and infants in sub-Saharan Africa.

The Phase III trials are currently underway in a number of African countries; if all goes to plan, the vaccine will be submitted for regulation by drug authorities as early as 2012. This information, and more, can be found courtesy of the Malaria Vaccine Initiative website: http://www.malariavaccine.org/index.php.

Malaria Vaccine

by

QUESTION:

Why is a vaccine against malaria seen as the main hope for the future?

ANSWER:

This answer is courtesy of a medical doctor assisting us with answering your questions.

A vaccine is seen as the great hope for the future because the malaria parasite has an extraordinary talent for developing resistance very rapidly against each class of drug that is introduced into the arsenal against it.  This is accomplished by various mechanisms, such as concentrating and pumping the drug back outside its outer membrane, mutation of drug binding sites rendering the drug molecules incapable of attaching to or entering the cell in order to do its work and alteration of other enzymes within the cell to change the pH  (acidity), again rendering certain drugs ineffective, even if they do get in (among other mechanisms!). That said, the development of an effective vaccine has been difficult due to changing surface proteins against which these vaccines are being developed.  In order to work, the vaccine has to be developed targeting highly “conserved” outer proteins which do not undergo genetic mutation frequently…ie, not so much of a moving target.