AFRO-NETS> Malaria Vaccine Trials Underway in Africa

[Manju Chatani <manju@hdnet.org>]

Malaria Vaccine Trials Underway in Africa
-----------------------------------------

IAVI Report - October/November 2002

Patricia Kahn
http://ww2.aegis.org/pubs/iavi/2002/IAVI2002-1004.html

While AIDS researchers often say that HIV is one of the most formida-
ble pathogens ever targeted for a vaccine, the same holds true for 
the parasites that cause malaria -- a disease that claimed 1 to 2 
million lives every year, 75% of them children under five.

One of the biggest obstacles for malaria vaccine developers is that 
they express between 5,000 and 6,000 proteins, compared to only 9 for 
HIV -- vastly complicating the task of determining which antigens to 
include in a vaccine. The parasites also show a high degree of ge-
netic diversity, which -- given their huge genome size -- has defied 
classification into groups analogous to HIV subtypes. And its complex 
life cycle encompasses three very different forms and a highly so-
phisticated strategy for evading the immune system through frequent 
switching of surface antigens.

Yet despite these immense challenges, two lines of evidence indicate 
that it is indeed possible to generate protective immunity against 
malaria parasites, which fall into four separate species of Plasmo-
dium (of which two are responsible for most disease). One is that 
highly-exposed people who survive multiple bouts of malaria in child-
hood gradually develop partial ("semi"-) immunity that reduces the 
severity of disease during later infections. Another is that infec-
tion can be blocked by immunization with irradiated sporozoites -- 
the parasite form that invades liver cells immediately after infec-
tion, where it replicates intracellularly for 1-2 weeks without in-
ducing symptoms. While this latter protection requires cellular immu-
nity (and can be transferred in mice via CD8 cells), natural semi-
immunity appears to depend mainly on antibodies to the merozoite, the 
form that enters the bloodstream and invades erythrocytes after in-
fected liver cells finally burst.

Attempting to exploit these findings, malaria researchers have devel-
oped vaccines based on both sporozoite and merozoite antigens, using 
some of the same new technologies used for HIV vaccines. And, thanks 
largely to support from Malaria Vaccine Initiative (Washington, DC), 
and the Wellcome Trust (UK) three of these candidates are now in 
clinical trials in Africa: two protein-based vaccines, including one 
that already showed significant but short-lived protection in an ef-
ficacy trial in Gambia, and another based on a DNA/MVA prime-boost 
approach, a widely-used strategy in the HIV field.

Some developers expect that these candidates may not be instant "home 
runs" conferring highly effective, long-lasting immunity. Rather, 
they could be contributors to a multi-component vaccine, seen by many 
as the more likely formula for success. "Most people in the field ex-
pect that an effective malaria vaccine will require targeting multi-
ple stages and antigens," says Dan Carucci, director of the Malaria 
Program at the US Naval Medical Research Center. While immune re-
sponses directed at sporozoite-infected liver cells could reduce the 
number of parasites entering the bloodstream, he adds, others aimed 
at the merozoite stage would blunt the severity of disease. In ba-
bies, the overall effect could be "to catapult their malaria immune 
status into that of adolescents," says malaria researcher Hermann Bu-
jard of the University of Heidelberg. Testing Malaria Vaccines

Determining vaccine efficacy is simpler for malaria than for HIV. 
Once a candidate's safety is established, first indications of effec-
tiveness may be gathered by challenging small numbers of vaccinated 
volunteers (at experienced research centers) under carefully con-
trolled conditions where they are bitten by infected mosquitoes; vol-
unteers who become infected are treated immediately with anti-
malarial drugs.

Gray Heppner, who heads the Malaria Vaccine Program at the Walter 
Reed Army Institute of Research (WRAIR, Rockville) where many of 
these challenge studies have been done, points out that it's a some-
what artificial model. The challenge uses a single strain of parasite 
at up to 10-fold the natural dose, to ensure that all volunteers are 
exposed to an infectious dose. What's more, volunteers at these US or 
European centers have no prior exposure to malaria, unlike people in 
endemic regions where a vaccine is most urgently needed. But preven-
tion or delay of infection is nonetheless a useful, albeit highly 
stringent, hint of efficacy, says Heppner.

Then comes the real test in endemic regions among semi-immune popula-
tions normally exposed to a wide diversity of circulating strains. In 
high-incidence regions, vaccine efficacy can be measured in small, 
short trials (compared to those needed for testing HIV vaccines). For 
example, in The Gambia, where malaria occurs only in the July-to-
November rainy season, about 60% of adults become infected during a 
single season, and efficacy trials require only a few hundred volun-
teers and about six months time.

GSK's Protein Subunit Vaccine

As the most advanced candidate now in African trials, GlaxoSmith-
Kline's so-called RTS,S vaccine contains about half of the major 
sporozoite coat protein fused to the Hepatitis B surface antigen. 
When formulated with GSK's AS02 adjuvant, challenge studies done col-
laboratively with the WRAIR found RTS,S to be about 50% effective in 
blocking infection with homologous sporozoites (i.e., of the same 
strain as the vaccine protein), and to protect one in five volunteers 
upon re-challenge 6 months later. Immune analysis detected strong an-
tibody responses and some cellular responses, including "modest" CD8 
levels, according to Joe Cohen, who directs GSK's program on vaccines 
against emerging diseases.

Moving to the field, safety studies in The Gambia were followed by a 
collaborative efficacy trial in 306 highly exposed male volunteers 
(Lancet 2001 Dec 8;358(9297):1927-34). The results: significant delay 
in time to infection, with about 70% protection in the first two 
months, but waning to zero by week 15. Re-vaccination of 158 volun-
teers the next year showed about 47% protection over 9 weeks. Protec-
tion extended beyond the vaccine strain to other, "unmatched" circu-
lating strains.

The vaccine was also tested in Gambian children, looking first at 
safety and dosage in 6-11-year olds, then in 1-4 year olds. Based on 
these results, Phase I studies are now underway in children in Mozam-
bique, where malaria is transmitted year-round rather than season-
ally; by the end of 2002, a Phase IIb pediatric study will begin to 
gather preliminary efficacy data. That trial will also introduce a 
new element, says Cohen: Rather than measuring only sterilizing immu-
nity, it will also look at endpoints reflecting severity of disease 
at the time children become ill and are brought to the clinic for 
treatment.

In the meantime, further work aims at improving the levels of CD8 T-
cell responses, for example through the use of other adjuvants and 
immunization schedules. And, in keeping with the goal of developing 
multi-component vaccines, small clinical studies are looking at 
prime-boost combinations with different candidates, including one in 
Oxford with the MVA-based vaccine described below.

Sporozoite Antigens in DNA/MVA Vaccines 

Another strategy now in efficacy studies is a prime-boost combination 
developed by Adrian Hill's group at Oxford University. The two vac-
cines encode a complete TRAP protein (Thrombospondin-Related Adhesion 
Protein), one of the main sporozoite antigens, downstream from 20 in-
dividual peptides containing mostly CD8 T-cell epitopes from six 
sporozoite or liver-stage antigens.

Multiple clinical studies resulted in an immunization regimen gener-
ating a 10-fold boost in T-cell Elispot numbers with DNA/MVA compared 
DNA or MVA alone, to levels in the 1,000 spots per million PBMC 
range; the better regimes (using DNA/MVA or fowlpox plus DNA) yielded 
broad strain cross-reactive results. About 100 volunteers in Oxford 
have now been challenged-in this case with a heterologous strain, re-
sulting in delay of average time to infection that corresponds to 
"substantial" reduction in the estimated numbers of parasites emerg-
ing from the liver. In addition, about 50-60 volunteers have been 
safely immunized in Phase I studies at the Medical Research Council 
Laboratories in Banjul, including 20 children who were given MVA 
alone. Results will be known in Spring 2003.

Also in development: the same vaccine antigens (TRAP and sporozoite 
coat protein) in fowlpox, which Hill says so far looks "as good, and 
maybe much better." Merozoite Protein-Based Vaccines

Will people vaccinated with one of two main strains of merozoite coat 
protein (MSP-1) also recognize the other one? That's the question be-
ing studied in WRAIR's ongoing 60-person trial, launched in Kenya in 
April 2002 in collaboration with the Kenya Medical Research Insti-
tute, MVI and USAID. The vaccine contains a portion of the MSP-1 pro-
tein formulated with GSK's AS02 adjuvant. Also in the pipeline: the 
first full-length MSP-1-based vaccines, made by Hermann Bujard's 
group at the University of Heidelberg, which synthesized the two main 
strains of this notoriously unclonable protein from scratch. The 
first clinical tests will be conducted in Tobingen, Germany and WRAIR 
before moving into trials in Burkina Faso. In addition to the pro-
tein-based MSP-1 vaccines, Bujard's group is developing MVA-based 
versions.

Finding the Right Antigens: Future Directions 

Since 1993, the US Navy's malaria program has been developing DNA-
based candidates, working towards the strategy of using cocktails 
containing plasmids with different antigens. With three Phase I tri-
als under their belts, their current vaccine contains 5 different an-
tigens (3 from sporozoites, 2 from merozoite); in parallel they are 
developing MVA- and adenovirus-based vectors as possible boosts, fol-
lowing encouraging protection results in monkeys. Other groups, in-
cluding WRAIR and the malaria program at NIAID (the US National In-
stitute of Allergy and Infectious Diseases) are studying additional 
antigens for clinical evaluation.

But as they work to improve immunogenicity of DNA-based vaccines, the 
Navy program is also seeking better ways to identify which antigens 
from the huge number of potential candidates might really matter, 
says Carucci. So far, studies of protected versus unprotected volun-
teers (from vaccination with irradiated sporozoites) have proved 
frustratingly inconclusive: the researchers find only low, although 
detectable, cellular responses to peptide pools from the few antigens 
they've looked at. "Maybe we're missing something big," says Carucci.

But the completion of the Plasmodium falciparum genome sequence of-
fers a way to approach the problem on a large scale rather than anti-
gen-by-antigen, he adds. Looking at the total pool of encoded pro-
teins, the researchers have identified over 1,000 new proteins, and 
are developing assays to screen the blood of protected volunteers for 
responses to any of them--so they can determine whether there is a 
dominant response that correlates with protection and also identify 
potential new antigenic targets. So far, they've found six new para-
site proteins on the surfaces of infected erythrocytes. Still, says 
Heppner, "we need more antigens, more adjuvants, to increase the mag-
nitude and duration of protection. And we need more money. So many 
good concepts are still restricted by lack of funds."

(c)2002. The IAVI Report.

Source: AEGiS

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