Policies for malaria vaccine

Policies in health management are very important for the day to day operation of any health organization. When dealing with diseases that are targeted for eradication by vaccination, like malaria, policies give a general direction in which to proceed. They include statements that identify the rules that govern vaccine manufacture and administration, and give reasons for why such rules exist. The policies are also expected to tell us when the vaccine rules apply and when they don't. They must tell us who is covered, who is not and the consequences of not being vaccinated.

Since an effective first generation vaccine against malaria is already in the works, (RTS,S/AS01 is in Phase III clinical trials right now), to begin utilizing it soon after licensure, severely affected endemic countries must have a time targeted policy in place by now.

The Malaria Vaccine Initiative (www.malariavaccine.org) has developed a tool for use by countries that helps expedite the decision making process. The tool, called the 'Malaria Vaccine Decision - Making Framework', helps in data collection, in time with the licensure process of the vaccine to ensure that the countries that need it are prepared and ready for it.

The tool basically divides data that can be collected into global data and national level data. Some of these like the impact of current interventions and their cost effectiveness are critical global data, that play a major part in the feasibility and success of eradication strategies. Other data such as national affordability, epidemiology profile by state/region/county are critical local data. By combining these, countries can start important processes and create the infrastructure needed. Important processes include establishing a technical working group at the national level, integrating the vaccine into the countries' multiyear strategic plan (on the basis of which funds get distributed at the national level), engaging local pharmaceutical companies, creating a national expert group on recommendations on vaccine introduction, creating advocacy groups, creating advertisements for extension activities etc.

Deciding to set up a vaccine plan or policy takes considerable time. A country cannot decide suddenly that they want to begin using the vaccine, without any formal rules in place. The progress in policy making and setting up a framework has been different in different countries. Here are some updates from some African countries (I acknowledge that the sampling of countries is biased. I chose these countries because I have friends from these places):

Uganda : has a nation specific framework in place and has a committee on malaria vaccines, that was established in 2009, that meets regularly.

Ghana :Held kick off consultations, created a national framework for decision making, created a technical working group which has met regularly since 2009 and is working to collect data on malaria vaccine introduction. Ghana is also a Phase III clinical trial testing site.

Kenya : Has held national stakeholder consultations to discuss trials and have revised the framework to suit their national conditions and are in the process of creating a working group. Kenya is also a testing site for the phase III trials

Zimbabwe : is yet to set up plans

There are other endemic nations that are potential candidate countries for vaccine introduction, but are sitting on the fence right now, because of the unavailability of data from phase III trials and licensure proceedings. Also, other diseases may be on their priority list because of ease of elimination and the availability of a licensed vaccine. For example, malaria is endemic in India, but the government is not scrambling to get a policy in place to be able use the malaria vaccine upon licensure. Reasons include the facts that malaria is not high on the priority list, is curable, has a complex lifecycle that involves invertebrate vectors (which have to be eliminated) and has a lower disease burden in terms of hospital hours and lost work hours, than say chikungunya (which is also transmitted by mosquitoes). On the other hand, polio which has a cheap, effective oral vaccine, has proven itself as an eradicatable disease in other parts of the world and so is an easier target.(The Indian government has policies in place for polio vaccination, which is now mandatory, with no exemptions. The policies were drawn up as a part of a five year plan. The importance of incorporating vaccine policies into long term plans cannot be emphasised enough, because that is the only way something can be achieved).

In conclusion, vaccine policies are meant to build up the health of people and lift communities as a whole. Just as little drops make an ocean, small decisions made at the right time can cause effects that are greater than one's imagination.

References :
 Malaria Vaccine Initiative http://www.malariavaccine.org/preparing-decision-making.php
http://www.malariavaccine.org/files/MVI-GSK-PhaseIIIfactsheetFINAL-web.pdf
Malaria Vaccine Decision making framework http://malvacdecision.net/2012/04/noor/
http://malvacdecision.net/see-the-progress-in-my-country/
http://malvacdecision.net/wp-content/themes/malaria-vaccine/DMF-data-and-processes-April2012.pdf

Vaccines - Sociological aspects

The readings for class 3 discussed some important reasons for the controversies that surround childhood vaccinations, highlighting issues such as vaccine ingredients, allergies and grouping these into nine pertinent categories. The readings also traced the roots of the problem and laid bare the theme at the center of it all : human nature.

With regard to the malarial vaccines, human social behaviour has been refined. Since there has been no vaccine commercially available so far, there has been no hue and cry yet.

The only malarial vaccine that has ever reached phase III clinical trials is the RTS,S, a subunit vaccine containing pre erythrocytic circumsporozoite protein (RTS) fused to the Hepatitis B surface antigen (B)  (Lell B et al., 2009; WHO, 2009).

INTENDED TARGET GROUPS
The vaccine when commercially available will be primarily used in countries where malaria is endemic. In countries like the United States, where malaria is not endemic, the vaccine will probably be made available to people intent on travelling to international locations that are endemic.

WILL VACCINE EFFICACY PLAY A ROLE IN ITS ACCEPTABILITY ?

The vaccine at the heart of the childhood vaccine controversy , the MMR vaccine, has an efficacy of >90 percent. In phase II clinical trials conducted in Kenya and Tanzania, the RTS, S ,vaccine had an efficacy of only 52.9 % in children aged 5 to 17 months , who had been given a primary dose and two boosters.  That is, only 53 people out of every 100 who are vaccinated could fight off an infection with wild type parasite. One could think that this could play a role in the acceptance of the vaccine by communities. It appears however that parents, in countries that are the intended target groups for the vaccine, perceive the risk of vaccination as being  lower than the risk of contracting the disease itself.

Studies in central Ghana suggest that parents prefer the vaccine over prophylactic malarial drugs and that they are willing to add malarial vaccines to the myriad of other vaccines their children receive (Febir L et al., 2013).

AWARENESS GAPS ....  WHERE EXPECTED, NONE EXIST !

Contrary to established narrow-minded expectations, field work in Mombazique showed that awareness about malaria and vaccines were very high.  To quote Bingham et al., 2012, "Vaccines are seen as means to reduce the threat of childhood illnesses and to keep children and the rest of the community healthy"

Properly disseminated knowledge and the experience that stems from facing the deadly disease have made the target population wise. They do not seem to have fallen prey to their own intellect like the few in developed nations who reject childhood vaccinations.

THE THING WITH DOSES AND INGREDIENTS

So far, three doses of the vaccine are required to achieve effective immunity. If newer more efficacious adjuvants are not available soon, the cost of protection could be extraordinarily high. This can result in policy constraints in immunizing adults as well as children.

Also, since the vaccine has subunit antigens there will be no multiplication inside the vaccinated human and no spread of immunity (the spread of live vaccine poliovirus  conferred immunity on exposed people as well). Herd immunity can be established only by vaccinating every individual.

To date, the adjuvant AS01, which contains monophosphoryl lipid A from LPS of Salmonella minnesota (Mata E. et al.,2013), has had a safe track record. But, if any adverse effect ever occurs, it can well be expected that the first ingredient in the vaccine that will be considered worthy of blame will be the adjuvant, since the proof of concept of using the RTS has been validated by use with other adjuvants such as AS02.

In conclusion, malarial vaccines will be well received when they are approved and marketed.

References

Lell B, Agnandji S, von Glasenapp I, Haertle S, Oyakhiromen S, Issifou S,
Vekemans J, Leach A, Lievens M, Dubois MC, Demoitie MA, Carter T, Villafana T,
Ballou WR, Cohen J, Kremsner PG. A randomized trial assessing the safety and
immunogenicity of AS01 and AS02 adjuvanted RTS,S malaria vaccine candidates in
children in Gabon. PLoS One. 2009 Oct 27;4(10):e7611.

Febir LG, Asante KP, Dzorgbo DB, Senah KA, Letsa TS, Owusu-Agyei S. Community
perceptions of a malaria vaccine in the Kintampo districts of Ghana. Malar J.
2013 May 7;12:156.

Bingham A, Gaspar F, Lancaster K, Conjera J, Collymore Y, Ba-Nguz A. Community
perceptions of malaria and vaccines in two districts of Mozambique. Malar J. 2012
Nov 28;11:394.

Mata E, Salvador A, Igartua M, Hernández RM, Pedraz JL. Malaria vaccine
adjuvants: latest update and challenges in preclinical and clinical research.
Biomed Res Int. 2013;2013:282913. doi: 10.1155/2013/282913. Epub 2013 Apr 23.
PubMed PMID: 23710439; PubMed Central PMCID: PMC3655447.

An overview of vaccines against malaria

IN THE NEWS

On 9 August 2013, CNN reported a breakthrough in malaria vaccinology. A new radiation attenuated intravenous vaccine has shown to be 100 % efficacious if injected in multiple doses. In about eight to ten years, this vaccine would be readily available at any pharmacy store. Before that, it has to pass rigorous tests of safety and must be approved by the FDA.

ARE WE THERE YET ?

Although it is relatively easy to produce updated flu vaccines every year, malaria vaccines have eluded decades of research. There have been many hurdles along the way. Some of these have been discussed in a paper by Thera and Plowe, titled "Vaccines for Malaria: How close are we? " published in the Annual Reviews in Medicine in November 2011.

The first obstacle is the size of the parasite's genome. The 5000 genes in Plasmodium falciparum's genome are organized into 14 chromosomes and there are roughly 23 million bases. This precludes the development of an efficient DNA vaccine. Successful DNA vaccines have so far only been developed against viruses and bacteria with much smaller genomes.

The complex lifecycle of Plasmodium also allows for differential gene expression. Like the Lyme disease parasite that shows antigenic (and phase variation), Plasmodium expresses highly variant antigens such as PfEMP1s that are coded by up to 60 var genes in the genome.

In the haploid liver stages and blood stages of the parasite, mutations occur during mitotic replication. Genetic recombination commonly occurs during the diploid sexual stages. Drugs used against Plasmodium also provide some amount of selection pressure and drive mutation of the parasite. From a single geographical location, it is possible to isolate up to 18 different forms of a surface antigen. Hence, potential surface epitope change and when these vaccine targets are lost or modified, older vaccines (in the case of malaria, which were never available to begin with) become obsolete.

Polymorphisms in surface antigens play important roles in determining strain specific immunity.

Malaria vaccines typically target a specific stage of the parasitic lifecycle and show effect only against that stage. However, even a single surviving parasite such as a sporozoite could multiply to produce thousands of merozoites in 48 hours and result in an infection.

THE STORY SO FAR ..

Vaccines against malaria that have been experimentally created fall under these main categories. Classification is based on the stage of protection, rather than the conventional classification of vaccine type.

> Pre Erythrocytic vaccines

>Blood stage vaccines

>Transmission blocking vaccines

>Whole organism vaccines

 (malariavaccine.org)

PRE ERYTHROCYTC VACCINES

RTS,S/ AS01 is an experimental subunit vaccine that targets the pre-erythrocytic circumsporozite protein CSP of Plasmodium falciparum. It consists of CSP (which has a central conserved region flanked by T cell epitopes) in Adjuvant System 01 (a proprietary adjuvant that contains monophosphoryl lipid A and QS21). This vaccine showed up to 60 % protection in field trials. It is currently in phase III trials in seven African countries.

To offer substantial protection, subunit vaccines have to be combined with strong adjutants. This in itself poses a risk of severe reactions against the adjuvant.

Other pre-erythrocytic vaccines that have passed preclinical and early clinical trials have not shown too much promise.

BLOOD STAGE VACCINES

These are usually based on antigens that coat the surface of the invasive merozoites or are involved in the hijacking of the erythrocyte. The merozoite surface protein 1 or MSP1 and the apical membrane antigen 1 or AMA 1 has both shown some promise as vaccine candidates.

Two AMA1 vaccines have passed the preclinical and clinical stages of development.

A vaccine directed against merozoites surface protein 3 has shown some efficacy against the clinical stage of malaria.

TRANSMISSION BLOCKING VACCINES

These vaccines target immunogenic epitopes on gametocytes and other mosquito stages that are important for the transmission of the parasite.

Although one such vaccine appeared to produce immunity by blocking transmission, the adjuvant that it was formulated with viz., Contained ISA 51 created safety issues by being extremely reactive.

MULTI STAGE MULTI ANTIGEN VACCINES

Plasmodium is a complex organism and so to be efficacious against different stages, a vaccine must target different antigens that are immunodominant at different stages of the organism.

SPf66 is one such vaccine. It is a synthetic vaccine that targets the CSP expressed in the pre-erythrocytic stage. SPf66 is derived from the MSP1 and hence is also protective in the erythrocytic stages.

WHOLE ORGANISM VACCINES

Although one would assume that this would be the direct approach to a vaccine against malaria, some of the early trials in which whole organisms were used were not interpreted as a direct path to a vaccine.

However, the report on CNN concerned a vaccine that was made from radiation attenuated, metabolically active, non-replicating cryopreserved sporozoites. This vaccine did not show protection when injected via the intradermal or subcutaneous routes. Intravenous route that mimicked the bite of a female mosquito showed the best effect. After delivery, the sporozoites were able to reach and replicate in the liver and induce protection.

A list of antigenic candidates that can be targeted and used in a vaccine  are listed here : http://www.hindawi.com/journals/bmri/2013/282913/tab2/

THE START OF A JOURNEY

Developing an efficient vaccine against malaria is not an end by itself. The vaccine is only a tool that will be useful in combating the deadly disease and will help in its eradication.


References : 

Thera MA, Plowe CV. Vaccines for malaria: how close are we? Annu Rev Med 2012;63:345-357.

Malaria vaccine initiative : http://www.malariavaccine.org/malvac-lifecycle.php

Malaria - the disease

Etiology

Malaria is caused by protozoae of the genus Plasmodium. It was traditionally believed that there are only four species that cause human malaria: Plasmodium falciparum, P. malariae, P.ovale and P.vivax. (WHO, 2013). A fifith species was isolated in 2010 and has been named P. knowlesi. (Kantele A, 2010). The four species have distinct morphological differences that aid in their diagnosis on a blood smear. (CDC, 2013).

Malaria is vector borne and the parasites can be transmitted by more than thirty species of Anopheline mosquitoes.

Epidemiology

Malaria is endemic in 104 countries . (WHO, 2012)

The average incubation period for malaria is 12 days (tropical strains) and 15 days (Temperate strains). (Lover AA, 2013)

Malaria is severe in children , immunosuppressed patients and pregnant women. Malaria in pregnant women can cause miscarriages, stillbirths and neonatal death. (WHO, 2013)

Lifecycle

Infectious sporozoites of the Plasmodium are carried by the Anopheles mosquito in its salivary glands. When the mosquito feeds on a human, it injects saliva and the sporozoites into the body. The sporozoites moves to their predilection site , the liver. There the sporozoites enter the hepatocytes and divide. They produce thousands of merozoites , which are haploid forms. These rupture the hepatocytes as they exit and enter the blood stream.

 

Erythrocyte invasion by merozites (Haldar et al.,2007)

The intraerythrocytic cycle of Plasmodium is clinically important. The receptors on the erythrocytes include Thrombospondin, CD36, ICAM-1, VCAM-1 and  ELAM-1.(Pasloske, 1994).  The erythrocytes infected with mature stages of Plamodium adhere to vascular endothelial cells in postcapillary venules. Infected erythrocytes can also form rosettes with uninfected erythrocytes.  In P.falciparum, the paraite matures to a trophozoite stage, which matures into schizonts, which eventually relaease 16-32 daughter merozoites on rupturing the RBC. These merozoites invade uninfected erythrocytes and  the cycle continues.

The sexual cycle occurs in the female mosquito, which feeds on the infected person. Some of the trophozoites differentiate into gametocytes in the erythrocytes. These gametocytes are ingested by the mosquito along with blood. They eventualy fuse in the midgut of the mosquito and form infective sporozoites, that can be transmitted. (Halder et al., 2006)

Malaria : Clinical stages

The acute disease presents as a febrile sickness. (WHO,2013). The intra erythrocytic cycle of the parasite is reflected as a cyclic pattern of fevers and chills. Other features of the disease include hypoglycemia, hyperlactermia, anemia and altered consciousness (Weatherall DJ, 2002 ; Haldar, 2006).  Levels of TNF alpha are high in malaria patients. TNF alpha enhances the expression of ICAM-1, VCAM-1 and ELAM-1 and is responsible for causing prodromal symptoms such as fever and nausea  (Pasloske, 1994)

The most severe disease is caused by P. falciparum. Clinical signs are nonspecific and include fever, chills, headaches, myalgia, vomoitng, cough , abdominal pain. Complications that arise from this infection include acute renal failure, pulomnary oedema, convulsons, shock, coma and death. Cerebral malaria is a complicated form of Plasmodium falciparum infection, found especially in children.

Malaria caused by P.vivax and P.ovale are not as life threatening as falciparum  malaria but are the major cause for relapsing malaria. These protozoae can remain dormant in the liver as persistent liver forms called hypnozoites. (WHO,2013)

Diagnosis

The WHO recommends definitive diagnosis either on the basis of microscopy or rapid diagnostic tests.
Plasmodium species can be detected on blood smears stained by simple Romanowsky stains such as Giemsa. Blood smears are easy and inexpensive to make. This method allows detection of various stages of the parasite and a rough quantification of parasite density. (WHO, 2013)
The Rapid Detection Tests detect specific antigens in the serum/blood. These tests can detect a single species at a time or multiple Plasmodium species.

Treatment
The disease is entirely preventatble and treatable. According to the " Guidelines for the Treatment of Malaria " Handbook published by the WHO in 2010, Arteminisin based combination therapies are recommended for uncomplicated cases. Combination therapies include Artemininsin in combination with lumefantrine, amodiaquine, mefloquine, sulfadoxine-pyrimethamine.  Duration of therapy must be atleast seven days.
Second line treatments recommended are artesunate with tetracycline/ doxycycline / clindamycin for 7 days.

Prevention

The main method of prevention so far has been vector control. Mosquitoes can be eliminated by insecticide spraying on breeding grounds. Transmission can be prevented by the use of individual insecticide treated mosquito nets.

Vaccines

    Subunit vaccines against malaria are being evaluated in clinical trials. These will be explored in                 subsequent posts.

 References:

 Kantele A, Jokiranta S. [Plasmodium knowlesi--the fifth species causing human

malaria]. Duodecim. 2010;126(4):427-34.

Weatherall DJ, Miller LH, Baruch DI, Marsh K, Doumbo OK, et al. 2002. Malaria and the red cell. Hematology Am. Soc. Hematol. Educ. Program 1:35–57

Pasloske BL, Howard RJ. Malaria, the red cell and the endothelium. Annu Rev Med. 1994; 45: 283-95

Haldar K, Murphy SC, Milner DA, Taylor TE. Malaria : mechanisms of erythrocytic infection and pathological correlates of severe disease. Annu Rev Pathol. 2007; 2 : 217-49

Lover AA, Coker RJ. Quantifying effect of geographic location on epidemiology of Plasmodium vivax malaria. Emerg Infect Dis [Internet]. 2013 Jul

WHO World Malaria Report 2012 (who.int/malaria/publications/world_malaria_report_2012/en/)