In the Journals

RTS,S/AS01-induced antibody titers predict long-term vaccine efficacy

Antibody titers generated from RTS,S/AS01, a malaria vaccine that targets Plasmodium falciparum circumsporozoite protein, predicted the efficacy of the vaccine, according to recent study data.

“This analysis shows that RTS,S/AS01-induced anti-circumsporozoite antibody titers can be used as a correlate of protection to predict vaccine efficacy over time.” Michael T. White, PhD, from the department of infectious disease epidemiology at Imperial College London, and colleagues wrote. “The estimated relationship between anti-circumsporozoite antibody titers and efficacy can be used to assess future versions of RTS,S and second generation anti-circumsporozoite vaccines.”

White and colleagues evaluated data on 8,922 children and 6,537 infants from Africa who were enrolled in a large phase 3 trial that assessed malaria transmission between 2009 and 2014. The researchers assessed causative factors associated with immunogenicity after RTS,S/AS01 vaccination, with or without a booster. Children received a primary dose of the RTS,S/AS01 vaccine when they were aged 5 to 17 months, and infants received the first dose at 6 to 12 weeks of age. A model of anti-circumsporozoite antibody trajectory, as well as naturally occurring development of protective immunity over time, was used to evaluate the relationship between clinical malaria and anti-circumsporozoite antibody titers.

After vaccination, children had higher RTS,S/AS01-induced antibody titers compared with infants (P < .0001), according to the results. Infants with higher baseline anti-circumsporozoite antibody titers were more likely to have lower anti-circumsporozoite antibody titers after receiving the vaccine, suggesting fetal exposure to maternal antibodies may hinder immunogenicity, the researchers wrote. The abundance of anti-circumsporozoite antibody titers after primary vaccination significantly predicted their abundance after the booster dose, which may be partially due to residual effects of priming, according to the researchers.

The researchers used a biphasic exponential model to characterize the dynamics of anti-circumsporozoite antibody titers after vaccination with or without a booster dose. According to the model, the short-term aspect of antibody responses rapidly diminished within the first 6 months, and the longer-term aspect waned over 4 years.

In children, the half-life of the short-term aspect of antibody response was 45 days (95% CI, 42-48) and the half-life of the long-lived aspect was 591 days (95% CI, 557-632). Twelve percent of the response was determined to be long-lived after primary vaccination, and increased to 30% after a booster dose. In infants, the researchers estimated that 7% of the response was long-lived after primary vaccination, which increased to 21% after the booster.

An estimated 50% of infections were avoided with an anti-circumsporozoite antibody titer of 121 EU/mL (95% CI, 98-153). Decreasing antibody titers were predictive of the duration of protection against clinical malaria across different age groups. In children, initial efficacy after vaccination was 74% (95% CI, 46-85) and declined to 28% (95% CI, 5-59) at 1 year, and 9% (95% CI, 1-32) after 5 years. In infants, efficacy was initially 63% (95% CI, 18-82) and declined to 11% (95% CI, 1-42) at 1 year, and 3% (95% CI, 1-19) after 5 years. A booster dose at 18 months was predicted to increase efficacy to 58% (95% CI, 8-80), resulting in 8% (95% CI, 1-35) vaccine efficacy at 5 years. The effectiveness decreased more in areas with higher disease transmission.

“The close concordance between data for clinical vaccine efficacy and anti-circumsporozoite antibody titers suggests that serological data might be used to assess future versions of RTS,S/AS01 and second-generation anti-circumsporozoite vaccines, despite the limitations of extrapolating to other populations and vaccines,” White and colleagues concluded. “This approach will be much faster and more cost effective than running larger and larger efficacy trials to test new variations in dose, schedule and adjuvant systems.” – by Jen Byrne

Disclosure: The trial was sponsored by GlaxoSmithKline and funded by GlaxoSmithKline and the PATH Malaria Vaccine Initiative. White reports being supported by fellowships from the Medical Research Council. Please see the full study for a list of all other authors’ relevant financial disclosures.

Antibody titers generated from RTS,S/AS01, a malaria vaccine that targets Plasmodium falciparum circumsporozoite protein, predicted the efficacy of the vaccine, according to recent study data.

“This analysis shows that RTS,S/AS01-induced anti-circumsporozoite antibody titers can be used as a correlate of protection to predict vaccine efficacy over time.” Michael T. White, PhD, from the department of infectious disease epidemiology at Imperial College London, and colleagues wrote. “The estimated relationship between anti-circumsporozoite antibody titers and efficacy can be used to assess future versions of RTS,S and second generation anti-circumsporozoite vaccines.”

White and colleagues evaluated data on 8,922 children and 6,537 infants from Africa who were enrolled in a large phase 3 trial that assessed malaria transmission between 2009 and 2014. The researchers assessed causative factors associated with immunogenicity after RTS,S/AS01 vaccination, with or without a booster. Children received a primary dose of the RTS,S/AS01 vaccine when they were aged 5 to 17 months, and infants received the first dose at 6 to 12 weeks of age. A model of anti-circumsporozoite antibody trajectory, as well as naturally occurring development of protective immunity over time, was used to evaluate the relationship between clinical malaria and anti-circumsporozoite antibody titers.

After vaccination, children had higher RTS,S/AS01-induced antibody titers compared with infants (P < .0001), according to the results. Infants with higher baseline anti-circumsporozoite antibody titers were more likely to have lower anti-circumsporozoite antibody titers after receiving the vaccine, suggesting fetal exposure to maternal antibodies may hinder immunogenicity, the researchers wrote. The abundance of anti-circumsporozoite antibody titers after primary vaccination significantly predicted their abundance after the booster dose, which may be partially due to residual effects of priming, according to the researchers.

The researchers used a biphasic exponential model to characterize the dynamics of anti-circumsporozoite antibody titers after vaccination with or without a booster dose. According to the model, the short-term aspect of antibody responses rapidly diminished within the first 6 months, and the longer-term aspect waned over 4 years.

In children, the half-life of the short-term aspect of antibody response was 45 days (95% CI, 42-48) and the half-life of the long-lived aspect was 591 days (95% CI, 557-632). Twelve percent of the response was determined to be long-lived after primary vaccination, and increased to 30% after a booster dose. In infants, the researchers estimated that 7% of the response was long-lived after primary vaccination, which increased to 21% after the booster.

An estimated 50% of infections were avoided with an anti-circumsporozoite antibody titer of 121 EU/mL (95% CI, 98-153). Decreasing antibody titers were predictive of the duration of protection against clinical malaria across different age groups. In children, initial efficacy after vaccination was 74% (95% CI, 46-85) and declined to 28% (95% CI, 5-59) at 1 year, and 9% (95% CI, 1-32) after 5 years. In infants, efficacy was initially 63% (95% CI, 18-82) and declined to 11% (95% CI, 1-42) at 1 year, and 3% (95% CI, 1-19) after 5 years. A booster dose at 18 months was predicted to increase efficacy to 58% (95% CI, 8-80), resulting in 8% (95% CI, 1-35) vaccine efficacy at 5 years. The effectiveness decreased more in areas with higher disease transmission.

“The close concordance between data for clinical vaccine efficacy and anti-circumsporozoite antibody titers suggests that serological data might be used to assess future versions of RTS,S/AS01 and second-generation anti-circumsporozoite vaccines, despite the limitations of extrapolating to other populations and vaccines,” White and colleagues concluded. “This approach will be much faster and more cost effective than running larger and larger efficacy trials to test new variations in dose, schedule and adjuvant systems.” – by Jen Byrne

Disclosure: The trial was sponsored by GlaxoSmithKline and funded by GlaxoSmithKline and the PATH Malaria Vaccine Initiative. White reports being supported by fellowships from the Medical Research Council. Please see the full study for a list of all other authors’ relevant financial disclosures.