User login
Photo by Caitlin Kleiboer
Results of a genomic sequencing analysis appear to explain why the malaria vaccine candidate RTS,S/AS01 (Mosquirix) is more effective in some children than others.
Researchers sequenced nearly 5000 patient samples and discovered that genetic variation in the protein targeted by RTS,S influences the vaccine’s ability to ward off malaria in young children.
The variation did not appear to affect the vaccine’s efficacy for infants.
Daniel E. Neafsey, PhD, of the Broad Institute in Cambridge, Massachusetts, and his colleagues reported these findings in NEJM.
RTS,S is designed to target a fragment of the protein circumsporozoite (CS), which sits on the surface of the Plasmodium falciparum parasite.
The CS protein is capable of provoking an immune response that can prevent parasites from infecting the liver, where they typically mature and reproduce before dispersing and invading red blood cells, leading to symptomatic malaria.
RTS,S aims to trigger that response as a way to protect against the disease. However, the CS protein is genetically diverse—perhaps due to its evolutionary role in the immune response—and RTS,S includes only one allele of the protein.
With their study, Dr Neafsey and his colleagues sought to test whether alleles of CS that matched the one targeted by RTS,S were linked with better vaccine protection.
The team obtained blood samples from 4985 of the approximately 15,000 infants and children who participated in the vaccine’s phase 3 trial between 2009 and 2013.
The researchers were sent samples when the first symptomatic cases appeared in those vaccinated, as well as samples from all participants at month 14 and month 20 following vaccination.
The team used polymerase chain reaction-based next-generation sequencing of DNA extracted from the samples to survey CS protein polymorphisms. And they set out to determine whether polymorphic positions and haplotypic regions within CS had any effect on the vaccine’s efficacy against first episodes of malaria within a year of vaccination.
The researchers found that RTS,S provided at least partial protection against all strains of P falciparum. However, the vaccine was significantly more effective at preventing malaria in children with matched allele parasites than those with mismatched allele parasites.
Among children who were 5 months to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% against malaria in which parasites matched the vaccine in the entire CS protein C-terminal, compared to 33.4% against mismatched malaria (P=0.04).
The same effect was not noted in infants. Among infants 6 weeks to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy.
Previous genetic studies conducted during RTS,S’s phase 2 trials had not detected an allele-specific effect for this vaccine candidate. The current study had a larger sample size, and recent technological advances made it possible to read the genetic samples with greater sensitivity.
“This is the first study that was big enough and used a methodology that was sufficiently sensitive to detect this phenomenon,” Dr Neafsey said. “Now that we know that it exists, it contributes to our understanding of how RTS,S confers protection and informs future vaccine development efforts.”
RTS,S is the first malaria vaccine candidate to complete phase 3 trials and receive a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use.
The vaccine was originally designed by scientists at GlaxoSmithKline in 1987. It is now being developed via a public-private partnership between GlaxoSmithKline and PATH Malaria Vaccine Initiative.
The current study was supported by the National Institute of Allergy and Infectious Diseases, the Bill & Melinda Gates Foundation, and the PATH Malaria Vaccine Initiative. 
Photo by Caitlin Kleiboer
Results of a genomic sequencing analysis appear to explain why the malaria vaccine candidate RTS,S/AS01 (Mosquirix) is more effective in some children than others.
Researchers sequenced nearly 5000 patient samples and discovered that genetic variation in the protein targeted by RTS,S influences the vaccine’s ability to ward off malaria in young children.
The variation did not appear to affect the vaccine’s efficacy for infants.
Daniel E. Neafsey, PhD, of the Broad Institute in Cambridge, Massachusetts, and his colleagues reported these findings in NEJM.
RTS,S is designed to target a fragment of the protein circumsporozoite (CS), which sits on the surface of the Plasmodium falciparum parasite.
The CS protein is capable of provoking an immune response that can prevent parasites from infecting the liver, where they typically mature and reproduce before dispersing and invading red blood cells, leading to symptomatic malaria.
RTS,S aims to trigger that response as a way to protect against the disease. However, the CS protein is genetically diverse—perhaps due to its evolutionary role in the immune response—and RTS,S includes only one allele of the protein.
With their study, Dr Neafsey and his colleagues sought to test whether alleles of CS that matched the one targeted by RTS,S were linked with better vaccine protection.
The team obtained blood samples from 4985 of the approximately 15,000 infants and children who participated in the vaccine’s phase 3 trial between 2009 and 2013.
The researchers were sent samples when the first symptomatic cases appeared in those vaccinated, as well as samples from all participants at month 14 and month 20 following vaccination.
The team used polymerase chain reaction-based next-generation sequencing of DNA extracted from the samples to survey CS protein polymorphisms. And they set out to determine whether polymorphic positions and haplotypic regions within CS had any effect on the vaccine’s efficacy against first episodes of malaria within a year of vaccination.
The researchers found that RTS,S provided at least partial protection against all strains of P falciparum. However, the vaccine was significantly more effective at preventing malaria in children with matched allele parasites than those with mismatched allele parasites.
Among children who were 5 months to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% against malaria in which parasites matched the vaccine in the entire CS protein C-terminal, compared to 33.4% against mismatched malaria (P=0.04).
The same effect was not noted in infants. Among infants 6 weeks to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy.
Previous genetic studies conducted during RTS,S’s phase 2 trials had not detected an allele-specific effect for this vaccine candidate. The current study had a larger sample size, and recent technological advances made it possible to read the genetic samples with greater sensitivity.
“This is the first study that was big enough and used a methodology that was sufficiently sensitive to detect this phenomenon,” Dr Neafsey said. “Now that we know that it exists, it contributes to our understanding of how RTS,S confers protection and informs future vaccine development efforts.”
RTS,S is the first malaria vaccine candidate to complete phase 3 trials and receive a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use.
The vaccine was originally designed by scientists at GlaxoSmithKline in 1987. It is now being developed via a public-private partnership between GlaxoSmithKline and PATH Malaria Vaccine Initiative.
The current study was supported by the National Institute of Allergy and Infectious Diseases, the Bill & Melinda Gates Foundation, and the PATH Malaria Vaccine Initiative.
Photo by Caitlin Kleiboer
Results of a genomic sequencing analysis appear to explain why the malaria vaccine candidate RTS,S/AS01 (Mosquirix) is more effective in some children than others.
Researchers sequenced nearly 5000 patient samples and discovered that genetic variation in the protein targeted by RTS,S influences the vaccine’s ability to ward off malaria in young children.
The variation did not appear to affect the vaccine’s efficacy for infants.
Daniel E. Neafsey, PhD, of the Broad Institute in Cambridge, Massachusetts, and his colleagues reported these findings in NEJM.
RTS,S is designed to target a fragment of the protein circumsporozoite (CS), which sits on the surface of the Plasmodium falciparum parasite.
The CS protein is capable of provoking an immune response that can prevent parasites from infecting the liver, where they typically mature and reproduce before dispersing and invading red blood cells, leading to symptomatic malaria.
RTS,S aims to trigger that response as a way to protect against the disease. However, the CS protein is genetically diverse—perhaps due to its evolutionary role in the immune response—and RTS,S includes only one allele of the protein.
With their study, Dr Neafsey and his colleagues sought to test whether alleles of CS that matched the one targeted by RTS,S were linked with better vaccine protection.
The team obtained blood samples from 4985 of the approximately 15,000 infants and children who participated in the vaccine’s phase 3 trial between 2009 and 2013.
The researchers were sent samples when the first symptomatic cases appeared in those vaccinated, as well as samples from all participants at month 14 and month 20 following vaccination.
The team used polymerase chain reaction-based next-generation sequencing of DNA extracted from the samples to survey CS protein polymorphisms. And they set out to determine whether polymorphic positions and haplotypic regions within CS had any effect on the vaccine’s efficacy against first episodes of malaria within a year of vaccination.
The researchers found that RTS,S provided at least partial protection against all strains of P falciparum. However, the vaccine was significantly more effective at preventing malaria in children with matched allele parasites than those with mismatched allele parasites.
Among children who were 5 months to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% against malaria in which parasites matched the vaccine in the entire CS protein C-terminal, compared to 33.4% against mismatched malaria (P=0.04).
The same effect was not noted in infants. Among infants 6 weeks to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy.
Previous genetic studies conducted during RTS,S’s phase 2 trials had not detected an allele-specific effect for this vaccine candidate. The current study had a larger sample size, and recent technological advances made it possible to read the genetic samples with greater sensitivity.
“This is the first study that was big enough and used a methodology that was sufficiently sensitive to detect this phenomenon,” Dr Neafsey said. “Now that we know that it exists, it contributes to our understanding of how RTS,S confers protection and informs future vaccine development efforts.”
RTS,S is the first malaria vaccine candidate to complete phase 3 trials and receive a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use.
The vaccine was originally designed by scientists at GlaxoSmithKline in 1987. It is now being developed via a public-private partnership between GlaxoSmithKline and PATH Malaria Vaccine Initiative.
The current study was supported by the National Institute of Allergy and Infectious Diseases, the Bill & Melinda Gates Foundation, and the PATH Malaria Vaccine Initiative.