Mosquirix (RTS,S): Vaccine to Prevent Plasmodium falciparum

Abstract and Introduction

Abstract

Objective: To summarize and evaluate the literature for Mosquirix (RTS,S) and provide insight into the therapeutic and economic controversies of this novel malaria vaccine candidate.
Data Sources: A systematic literature search was performed using the terms Mosquirix; RTS,S; malaria; vaccine; and Plasmodium in MEDLINE (1948-November 2011), EMBASE (1980-November 2011), International Pharmaceutical Abstracts (1970-November 2011), Google, and Google Scholar.
Study Selection and Data Extraction: Clinical trials describing vaccine development, pharmacology, pharmacokinetics, efficacy, and safety were reviewed. For efficacy, clinical trials were reviewed that reported acquisition of malarial disease. Information regarding study design, population, study period, baseline characteristics, clinical outcomes, results, and assessors of quality was extracted.
Data Synthesis: Five randomized controlled trials and 4 follow-up extension studies were identified. In Phase 2 trials, vaccine efficacy rates were 33–65% in infants and 30–53% in children for preventing the first episode of clinical disease. In Phase 3 trials, vaccine efficacy was 56% in children aged 5–17 months. RTS,S reduced the number of clinical malaria episodes and prevented severe malaria in several studies. The follow-up period for vaccine efficacy ranged from 6 to 45 months. RTS,S 25 μg is administered intramuscularly as 3 injections given 1 month apart for infants and children. RTS,S appears to be generally well tolerated. A few cases of meningitis and seizures (within 7 days of vaccination) have been reported.
Conclusions: RTS,S has demonstrated efficacy and safety in Phase 1, 2, and 3 trials, and has the potential to decrease morbidity and mortality from malaria worldwide. Major challenges include determination of the duration of immunity, assessment of its cost-effectiveness, its use in special populations, and its dissemination in endemic regions. Pending further studies, RTS,S has the potential to become the benchmark as the first effective vaccine against malaria.

Introduction

Malaria is one of the most significant infectious disease burdens worldwide. The World Health Organization (WHO) reported 247 million cases of malaria in 2008, resulting in approximately 1 million deaths.^[1] The disease especially targets the most vulnerable groups, namely infants and children, and accounts for approximately 20% of childhood deaths in Africa. Many people living in countries where malaria is endemic are unable to afford, or do not have access to, medications needed for treatment, which contributes to high morbidity and mortality. Furthermore, malaria has a devastating economic impact, with gross domestic products decreasing up to 1.3% in highly affected countries.

The 4 most common causes of malaria in humans are Plasmodium falciparum, P. vivax, P. malaria, and P. ovale. P. falciparum is the most fatal and represents the most common infection in Africa.^[2] The P. falciparum life cycle consists of 2 stages: asymptomatic hepatic (pre-erythrocytic), followed by symptomatic blood (erythrocytic) stage^[3] (Figure 1). During the erythrocytic phase, patients commonly present with fever, chills, weakness, headache, nausea, vomiting, and diarrhea. While erythrocyte stages are most responsible for these observable clinical symptoms, damage to hepatocytes and hepatomegaly may occur due to hepatic invasion during pre-erythrocyte phases.^[4] A model vaccine would aim to target the parasite prior to development of hepatocellular damage.

(Enlarge Image)

Figure 1.

The lifecycle of Plasmodium falciparum in the human host. (1) Sporozoites are introduced from an infected Anopheles mosquito, while taking a blood meal; (2) sporozoites migrate to the hepatic circulation and infiltrate neighboring hepatocytes; (3) sporozoites undergo development and differentiation in the hepatocytes, producing thousand of merozoites; (4) merozoites are liberated from the hepatocyte in small cellular vesicles called merosomes, which disintegrate in the systemic circulation releasing the merozoites; (5) merozoites invade erythrocytes and continue maturation and division to become schizonts; the red blood cell ruptures resulting in the systemic release of more merozoites, that infect more erythrocytes; (6) some merozoites differentiate into male and female gametocytes; (7) gametocytes are then consumed by uninfected female Anopheles mosquito during a blood meal; cycle is then repeated.

Development of malaria vaccines to prevent infection has been an area of intensive research. Studies assessing potential targets and immune responses escalated throughout the 1980s and 1990s. Unfortunately, complexity of infection and variability in immunogenicity have limited the utility of potentially effective candidate vaccines.^[5] However, recent advancements in antigen and adjuvant development have overcome many of these initial barriers and resulted in development of an innovative vaccine candidate.

Mosquirix (RTS,S) is a vaccine developed by Glaxo-SmithKline Inc. (GSK) in partnership with the PATH Malaria Vaccine Initiative as a preventive measure against P. falciparum clinical disease for infants and children living in endemic regions. It is the first malaria vaccine to reach Phase 3 trials and is currently being studied in ongoing clinical trials in Africa.^[6] Results from these studies will provide regulatory bodies with data necessary to make decisions on preventive strategies and management. However, many controversies need to be addressed before the vaccine can be distributed and administered to patients in endemic areas. The objective of this review is to summarize and evaluate the literature pertaining to RTS,S and provide insight into therapeutic and economic controversies of this novel vaccine.

Table 1. Vaccine Efficacy Results from Clinical Trials
Reference	Population	Follow-up Duration	Study Period	Outcome	Vaccine Efficacy 95% CI) (Per-protocol)	Vaccine Efficacy (95% CI) (ITT)
Phase 1 and 2 trials
Alonso (2004)¹⁰	2022 children from Mozambique	8.5 months after 1st dose	April 2003-May 2004	First episode of fever and parasitemia >2500 parasites/μL (Cohort 1)	29.9% (11.0 to 44.8); n = 1490	30.2% (14.4 to 43.0); n = 1605
		6.5 months after 3rd dose		First episode of parasitemia >0 parasites/μL (Cohort 2)	45.0% (31.4 to 55.9); n = 367	NR
				Several episodes of fever and parasitemia >2500 parasites/μL (Cohort 1)	27.4% (6.2 to 43.8); n = 1490	NR
Alonso (2005)¹⁵	2022 children from Mozambique	18 months after 3rd dose		First or only episode of fever and parasitemia >2500 parasites/μL (Cohort 1)	35.3% (21.6 to 46.6); n = 1442	32.8% (20.1 to 43.4); n = 1605
				Several episodes of fever and parasitemia >2500 parasites/μL (Cohort 1)	29.8% (13.8 to 42.8); n = 1442	32.4% (17.6 to 44.5); n = 1605
Sacarlal (2009)¹⁶	2022 children from Mozambique	45 months after 1st dose	First or only episode of fever and parasitemia >2500 parasites/μL	30.5% (18.9 to 40.4); n = 1490	NR
				Several episodes of fever and parasitemia >2500 parasites/μL	25.6% (11.9 to 37.1); n = 1490	NR
Bejon (2008)¹¹	894 children from Kenya/Tanzania	Mean 7.9 months	March 2007-August 2007	First or only episode of fever and parasitemia >2500 parasites/μL	53% (28 to 69); n = 809	49% (26 to 65) (unadjusted); n = 894
				Multiple episodes of fever and parasitemia >2500 parasites/μL	56% (31 to 72); n = 809	54% (31 to 69) (unadjusted); n = 894
Olotu (2011)¹⁷	894 children from Kenya/Tanzania	12 months after 3rd dose		First or only episode of fever and parasitemia >2500 parasites/μL	39% (20 to 54); n = 835	39% (20 to 53) (unadjusted); n = 894
				Multiple episodes of fever and parasitemia >2500 parasites/μL	42% (22 to 57); n = 835	44% (24 to 58); n = 894
		15 months after 3rd dose (Kenyan cohort only)		First or only episode of fever and parasitemia >2500 parasites/μL	46% (24 to 61); n = 415	37% (14 to 55); n = 447
				Multiple episodes of fever and parasitemia >2500 parasites/μL	51% (29 to 66); n = 415	44% (20 to 61); n = 44
Abdulla (2008)¹²	340 infants from Tanzania	6 months after 3rd dose	July 2006-February 2008	First or only episode of fever and parasitemia >500 parasites/μL	43.2% (−47.1 to 78.0); n = 297	41.8% (−32.9 to 74.6); n = 340
				Any infection (any level of parasitemia)	65.2% (20.7 to 84.7); n = 297	NR
Aponte (2007)¹³	214 infants from Mozambique	6 months after 3rd dose	June 2005-March 2007	First or only episode of fever and parasitemia >500 parasites/μL	65.8% (25.3 to 84.4); n = 185	NR
				Any infection (any level of parasitemia)	65.9% (42.6 to 79.8); n = 185	NR
Aide (2010)¹⁸	214 infants from Mozambique	1 year after 3rd dose		First or only episode of fever and parasitemia >500 parasites/μL	33.0% (−4.3 to 56.9); n = 177	25.9% (−9.9 to 50.0); n = 214
				Multiple episodes of fever and parasitemia >500 parasites/μL	25.9% (−15.7 to 52.6); n = 177	24.3% (−12.9 to 49.2); n = 214
Phase 3 trial
Agnandji (2011)¹⁴	6000 children aged 5–17 months from 7 African countries (total study population: 15,460)	12 months after 3rd dose	Randomization from March 2009 to January 2011	First or only episode of fever and parasitemia >5000 parasites/μL	55.8% (97.5% CI 51.3 to 59.8); n = 4296	50.4% (45.8 to 54.6); n = 6000
				First or only episode of fever and parasitemia >0 parasites/μL	54.1% (49.9 to 57.9); n = 4296	NR
				All episodes of fever and parasitemia >5000 parasites/μL	55.1% (50.5 to 59.2); n = 4296	53.9% (49.6 to 57.8); n = 600o

Table 1. Vaccine Efficacy Results from Clinical Trials

Reference

Population

Follow-up Duration

Study Period

Outcome

Vaccine Efficacy 95% CI) (Per-protocol)

Vaccine Efficacy (95% CI) (ITT)

Phase 1 and 2 trials

Alonso (2004)¹⁰

2022 children from Mozambique

8.5 months after 1st dose

April 2003-May 2004

First episode of fever and parasitemia >2500 parasites/μL (Cohort 1)

29.9% (11.0 to 44.8); n = 1490

30.2% (14.4 to 43.0); n = 1605

6.5 months after 3rd dose

First episode of parasitemia >0 parasites/μL (Cohort 2)

45.0% (31.4 to 55.9); n = 367

Several episodes of fever and parasitemia >2500 parasites/μL (Cohort 1)

27.4% (6.2 to 43.8); n = 1490

Alonso (2005)¹⁵

2022 children from Mozambique

18 months after 3rd dose

First or only episode of fever and parasitemia >2500 parasites/μL (Cohort 1)

35.3% (21.6 to 46.6); n = 1442

32.8% (20.1 to 43.4); n = 1605

Several episodes of fever and parasitemia >2500 parasites/μL (Cohort 1)

29.8% (13.8 to 42.8); n = 1442

32.4% (17.6 to 44.5); n = 1605

Sacarlal (2009)¹⁶

2022 children from Mozambique

45 months after 1st dose

First or only episode of fever and parasitemia >2500 parasites/μL

30.5% (18.9 to 40.4); n = 1490

Several episodes of fever and parasitemia >2500 parasites/μL

25.6% (11.9 to 37.1); n = 1490

Bejon (2008)¹¹

894 children from Kenya/Tanzania

Mean 7.9 months

March 2007-August 2007

First or only episode of fever and parasitemia >2500 parasites/μL

53% (28 to 69); n = 809

49% (26 to 65) (unadjusted); n = 894

Multiple episodes of fever and parasitemia >2500 parasites/μL

56% (31 to 72); n = 809

54% (31 to 69) (unadjusted); n = 894

Olotu (2011)¹⁷

894 children from Kenya/Tanzania

12 months after 3rd dose

First or only episode of fever and parasitemia >2500 parasites/μL

39% (20 to 54); n = 835

39% (20 to 53) (unadjusted); n = 894

Multiple episodes of fever and parasitemia >2500 parasites/μL

42% (22 to 57); n = 835

44% (24 to 58); n = 894

15 months after 3rd dose (Kenyan cohort only)

First or only episode of fever and parasitemia >2500 parasites/μL

46% (24 to 61); n = 415

37% (14 to 55); n = 447

Multiple episodes of fever and parasitemia >2500 parasites/μL

51% (29 to 66); n = 415

44% (20 to 61); n = 44

Abdulla (2008)¹²

340 infants from Tanzania

6 months after 3rd dose

July 2006-February 2008

First or only episode of fever and parasitemia >500 parasites/μL

43.2% (−47.1 to 78.0); n = 297

41.8% (−32.9 to 74.6); n = 340

Any infection (any level of parasitemia)

65.2% (20.7 to 84.7); n = 297

Aponte (2007)¹³

214 infants from Mozambique

6 months after 3rd dose

June 2005-March 2007

First or only episode of fever and parasitemia >500 parasites/μL

65.8% (25.3 to 84.4); n = 185

Any infection (any level of parasitemia)

65.9% (42.6 to 79.8); n = 185

Aide (2010)¹⁸

214 infants from Mozambique

1 year after 3rd dose

First or only episode of fever and parasitemia >500 parasites/μL

33.0% (−4.3 to 56.9); n = 177

25.9% (−9.9 to 50.0); n = 214

Multiple episodes of fever and parasitemia >500 parasites/μL

25.9% (−15.7 to 52.6); n = 177

24.3% (−12.9 to 49.2); n = 214

Phase 3 trial

Agnandji (2011)¹⁴

6000 children aged 5–17 months from 7 African countries (total study population: 15,460)

12 months after 3rd dose

Randomization from March 2009 to January 2011

First or only episode of fever and parasitemia >5000 parasites/μL

55.8% (97.5% CI 51.3 to 59.8); n = 4296

50.4% (45.8 to 54.6); n = 6000

First or only episode of fever and parasitemia >0 parasites/μL

54.1% (49.9 to 57.9); n = 4296

All episodes of fever and parasitemia >5000 parasites/μL

55.1% (50.5 to 59.2); n = 4296

53.9% (49.6 to 57.8); n = 600o

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Mosquirix (RTS,S)

A Novel Vaccine for the Prevention of Plasmodium falciparum Malaria

Abstract and Introduction

Abstract

Introduction

Tables

References

Authors and Disclosures

Authors and Disclosures

Figure 1.

Figure 1.

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