Antibody responses to the RTS,S/AS01E vaccine and Plasmodium falciparum antigens after a booster dose within the phase 3 trial in Mozambique

Abstract

The RTS,S/AS01 E vaccine has shown consistent but partial vaccine efficacy in a pediatric phase 3 clinical trial using a 3-dose immunization schedule. A fourth-dose 18 months after the primary vaccination was shown to restore the waning efficacy. However, only total IgG against the immunodominant malaria vaccine epitope has been analyzed following the booster. To better characterize the magnitude, nature, and longevity of the immune response to the booster, we measured levels of total IgM, IgG, and IgG 1-4 subclasses against three constructs of the circumsporozoite protein (CSP) and the hepatitis B surface antigen (HBsAg, also present in RTS,S) by quantitative suspension array technology in 50 subjects in the phase 3 trial in Manhiça, Mozambique. To explore the impact of vaccination on naturally acquired immune responses, we measured antibodies to P. falciparum antigens not included in RTS,S. We found increased IgG, IgG1, IgG3 and IgG4, but not IgG2 nor IgM, levels against vaccine antigens 1 month after the fourth dose. Overall, antibody responses to the booster dose were lower than the initial peak response to primary immunization and children had higher IgG and IgG1 levels than infants. Higher anti-Rh5 IgG and IgG 1-4 levels were detected after the booster dose, suggesting that RTS,S partial protection could increase some blood stage antibody responses. Our work shows that the response to the RTS,S/AS01 E booster dose is different from the primary vaccine immune response and highlights the dynamic changes in subclass antibody patterns upon the vaccine booster and with acquisition of adaptive immunity to malaria.

Advancements in protein nanoparticle vaccine platforms to combat infectious disease

“…Naturally acquired immunity against malaria is mediated by IgG levels and can be gained with age and exposure, decreasing risk of morbidity and mortality in adults; however, because children and infants may lack such protection, vaccination is important in this patient group (Dobano et al, 2019; Doolan, Dobano, & Baird, 2009). In recent years, clinical trials utilizing RTS,S/AS01 have examined safety, efficacies, immunogenicity, as well as a multitude of unique immune responses (Asante et al, 2020; Sanchez et al, 2020). Immune responses including unique antibody responses after variable doses and unique avidities of antibodies have been well documented (Dobano et al, 2019; Dobano, Ubillos, et al, 2019; Sanchez et al, 2020).…”

“…In recent years, clinical trials utilizing RTS,S/AS01 have examined safety, efficacies, immunogenicity, as well as a multitude of unique immune responses (Asante et al, 2020; Sanchez et al, 2020). Immune responses including unique antibody responses after variable doses and unique avidities of antibodies have been well documented (Dobano et al, 2019; Dobano, Ubillos, et al, 2019; Sanchez et al, 2020). RTS,S vaccination of young children in Africa results in higher specific IgG antibody titers, correlating with increased protection against clinical malaria (Dobano, Ubillos, et al, 2019).…”

“…In this comprehensive review, we showcase the protein NPs that are being investigated for development into vaccine platforms for numerous infectious diseases, specifically focusing on self‐assembling protein NPs, different types of VLPs (Figure 2), and how they stimulate immune responses to vaccination. Furthermore, we discuss human‐infecting viral vectors and their approved use as vaccine platforms for a number of infectious diseases (Ollmann Saphire, 2020; Sanchez et al, 2020). Although others have also used these protein NP platforms as frameworks for drug and gene delivery systems (Lee et al, 2017; Molino & Wang, 2014; Ren, Kratz, & Wang, 2011), our main focus in this review is to highlight the investigations of protein NPs as structural scaffolds upon which to develop new vaccines.…”

Impacts of Ecology, Parasite Antigenic Variation, and Human Genetics on RTS,S/AS01e Malaria Vaccine Efficacy

“…Anti-CSP antibody titers are positively correlated with protection and, though no threshold for protection was found, an antibody titer of 121 EU/mL (95% CI: 98–153) was estimated to prevent 50% of infections [ 18 •]. In one study, the fourth dose resulted in increased IgG1, IgG3, and IgG4 levels against all vaccine antigens after 1 month, but it did not increase IgG2 or IgM levels [ 19 ]. The complement response was most strongly correlated with IgG1 and, to a lesser extent, IgG3.…”

In silico identification of novel open reading frames in Plasmodium falciparum oocyte and salivary gland sporozoites using proteogenomics framework

“…Unfortunately, both vaccines and treatment options with drugs are limited due to the biological complexity of the Apicomplexan parasites [4]. Even for the wellstudied Plasmodium species, there is only one vaccine targeted for malaria with relatively low efficacy [5,6]. The complexity arises from the highly regulated life cycles that allow them to inhabit different hosts and intracellular niches [7].…”