Malaria is a communicable vector-borne disease caused by Plasmodium falciparum, a protozoan parasite that is transmitted to humans via Anopheles mosquitoes. The reported case incidence and associated deaths have declined globally over the years, but malaria is still a major threat to communities in affected areas. In 2017, malaria cases were reported to occur in 87 countries with an estimated 435,000 deaths of children under the age of five (WHO, 2018). Development of a protective vaccine has been challenging and currently there is no licensed malaria vaccine. Among vaccines in development, the RTS,S/AS01 vaccine is the most advanced and is now part of a large-scale pilot implementation program in children in selected African countries. This vaccine includes three main components: a) portions of the circumsporozoite protein (CSP) of Plasmodium falciparum, which is the primary surface antigen (Ag) on the sporozoites; b) hepatitis B surface antigen (HB); and c) a proprietary AS01B adjuvant from GlaxoSmithKline (GSK). The adjuvant is composed of 3-O-desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota and a saponin molecule (QS-21) purified from an extract from the plant Quillaja saponaria, combined in a liposomal formulation consisting of dioleoyl phosphatidylcholine and cholesterol in phosphate-buffered saline solution (Vekemans et al., 2009). A vaccine delivery regimen in which three doses of RTS,S/AS01B are given on a 0, 1, 2 month schedule was found to provide nearly 50% protection in controlled human malaria infection (CHMI) trials (Kester et al., 2009; Ockenhouse et al., 2015). In the field, however, a Phase 3 trial of RTS,S/AS01 vaccine using the same dosing schedule showed only modest efficacy of 30.1% in 6–12-week-old infants (Agnandji et al., 2012).

In search of better efficacy, a recent CHMI trial of RTS,S/AS01 vaccine (Malaria-071, NCT01857869) was designed to compare the standard (STD) 0, 1, 2 month dosing regimen with a delayed fractional dose (DFD) regimen in which the third dose was one fifth of the standard dose and was administered at 7 months after the second dose (Regules et al., 2016). The rationale for testing the DFD regimen was based on a prior study from 1997 that had found that delaying and reducing the third immunization dose enhanced the immunogenicity of RTS,S vaccine and achieved efficacy to 86% (Stoute et al., 1997). Interestingly, Malaria-071 confirmed the earlier findings and the DFD regimen again showed 86% efficacy, which was significantly greater than the 62.5% protection observed in the STD regimen. To understand the factors associated with protection against Plasmodium infection, a number of immunologic investigations were conducted in a blinded manner.

The present study focused on assessing the role of peripheral T follicular helper (pTfh) cells and B cells, because a prior CHMI trial of the RTS,S vaccine had found an association of anti-CSP antibody titers and CSP-specific CD4 T cells with protection (White et al., 2013). In Malaria-071, antibodies of higher avidity were elicited in the DFD regimen in association with higher somatic hypermutation of B cells, suggesting fundamental changes in the maturation of B cell affinity (Regules et al., 2016). High-affinity antibodies are generated from long-lived plasma cells and memory B cells that are produced after antigen-primed B cells undergo cognate interaction with T follicular helper cells (Tfh). This interaction occurs in the germinal centers (GC) of secondary lymphoid organs (reviewed in Crotty, 2011), causing the B cells to proliferate followed by isotype switching and somatic hypermutation. Many properties of lymphoid Tfh cells, including B cell helper function for antibody (Ab) generation (Crotty, 2011), are also present in a subset of circulating CD4 T cells designated as pTfh cells that are considered as having emigrated from the lymphoid pool into the peripheral circulation (Vella et al., 2019; Pahwa, 2019). To investigate their role in human vaccine trials, pTfh in circulation serve as an attractive alternative to lymphoid Tfh, which require lymph node biopsies (Bentebibel et al., 2016; Bentebibel et al., 2013; Herati et al., 2017; Herati et al., 2014; Pallikkuth et al., 2017; Pallikkuth et al., 2012; Pallikkuth et al., 2019; Boswell et al., 2014; Cubas et al., 2013; Locci et al., 2013; Simpson et al., 2010; Ueno, 2016).

Only a few studies of pTfh have been performed in the context of immunogenicity and the efficacy of malaria vaccines. In a murine model, a nanoparticle-based vaccine presenting recombinant P. vivax CSP led to a protective immune response, characterized by enhanced GC formation with expansion and differentiation of antigen-specific Tfh cells (Moon et al., 2012). A malaria vaccine study in humans involving RTS,S/AS01 alone or co-administered with different viral-vectored vaccines showed that skewing of pTfh cells towards a CXC chemokine receptor 3 (CXCR3⁺) Th1 phenotype was associated with reduced Ab quantity and quality and lower vaccine efficacy (Bowyer et al., 2018). More recently, in a phase III trial of the GSK malaria vaccine ‘Mosquirix’ in Tanzania and Mozambique, children with increased frequencies of pTfh and plasmablasts at the time of vaccination exhibited higher Ab titers (Hill et al., 2020). An important role was ascribed to antigen-specific pTfh and their cytokine profile in influenza vaccine-induced antibody responses (Pallikkuth et al., 2019). In the present study, investigation of the dynamics of CSP-specific pTfh and B cell responses in the DFD and STD regimens of Malaria-071 (Regules et al., 2016), pre- and post-vaccination, revealed key immune features that were linked with protection after sporozoite challenge and provided insight into the superiority of the DFD regimen.

Malaria is a leading cause of morbidity and mortality in endemic areas, underscoring the need for an effective vaccine. The RTS,S/AS01 vaccine is a promising candidate that has undergone extensive testing to define an optimal dosing and vaccine delivery strategy. In Malaria-071, a CHMI trial, participants in the DFD group who received a delayed and reduced third dose achieved 86% efficacy, which was significantly greater than the 62.5% protection attained under the STD regimen in which three vaccine doses are given at monthly intervals (Regules et al., 2016). To understand whether there was an immunologic basis to explain this difference, we conducted a study to examine T–B cell interactions in PBMC obtained from timed blood samples in the two regimens. For T cells, our focus was on delineating the dynamics of CSP antigen-specific pTfh cells, which were defined by phenotype and function. For B cells, we examined B cell maturation markers to define subsets and evaluated their function. A data integration approach was used to define correlates of vaccine-induced protection and non-protection. We found that protected subjects in both vaccine regimens were characterized by early induction of CSP antigen-specific pTfh responses, followed by functional memory B cell responses preceding the third dose that persisted at later time points. The non-protected subjects in both the DFD and STD regimens failed to mount the early pTfh response or B cell responses, pointing to the importance of pTfh in vaccine-induced protection. A key finding that provided insight into the inferiority of STD regimen was that in some NP subjects an initial ‘protective’ type of immune response was elicited by doses 1 and 2, but was aborted following the third vaccination dose. Understanding the mechanisms by which delaying and reducing the third antigen dose of RTS,S/AS01 after initial priming/boost helps to preserve the B cell immunity will lead to improved vaccination strategies. Our study was performed in a controlled setting with uninfected adult volunteers. Only field trials can tell us how such strategies will translate in endemic areas of the world where malaria exposure is rampant.

We noticed a clear increase in total pTfh cells and CSP-specific pTfh cells as early as 6 days post-first dose of RTS,S/AS01 vaccination that occurred only in participants who were protected following experimental challenge with P. falciparum. Circulating pTfh cells provide a snapshot of Tfh at the lymphoid inductive sites (Vella et al., 2019; Pahwa, 2019). Studies in healthy adults have documented the importance of pTfh expansion at day 7 or day 28 post-influenza and after other vaccines as well as bouts of various infectious diseases (Bentebibel et al., 2016; Bentebibel et al., 2013; Herati et al., 2017; Herati et al., 2014; Pallikkuth et al., 2017; Pallikkuth et al., 2012; Pallikkuth et al., 2019; Boswell et al., 2014; Cubas et al., 2013; Locci et al., 2013; Simpson et al., 2010; Ueno, 2016). The pTfh expansion was noted in both the DFD and STD regimens and was sustained throughout the vaccination schedule. This observation is reminiscent of the early induction of Ebola virus-specific pTfh following a single dose of the rVSV-Zaire Ebolavirus (ZEBOV) vaccine in an endemic population in Guinea, which was associated with protection (Farooq et al., 2016).

We identified pTfh phenotypically by CXCR5 expression in memory CD4 T cells. Cellular markers that have been used to define pTfh cells and their subsets have varied, with CXCR5 being a universally accepted receptor on these cells (Vella et al., 2019; Pahwa, 2019; Bentebibel et al., 2016; Herati et al., 2017; Locci et al., 2013; Pallikkuth et al., 2012; Heit et al., 2017; He et al., 2013; Morita et al., 2011; Moysi et al., 2018). Tfh cells that are located in the GC of secondary lymphoid organs (Vella et al., 2019; Pahwa, 2019; Herati et al., 2017; Herati et al., 2014; Heit et al., 2017) express high levels of PD-1. The frequency of PD-1⁺ cells is very low in circulating pTfh cells and the use of PD-1 as an essential marker that defines pTfh is likely to limit the frequency of identifiable pTfh. Moreover, the relevance of PD-1-expressing pTfh remains unclear because the molecule was found to be inhibitory for pTfh function in some studies (de Armas et al., 2017a). We have found that the expression of PD-1 in combination with that of the activation markers CD38 and HLADR in pTfh is inhibitory for their function in healthy volunteers given influenza vaccine (Pallikkuth et al., 2019). In light of this information, we opted to focus on the antigen-specificity of pTfh cells to mark functional cells. An important aspect of our analysis was the determination of CD40L expression, intracellular IL-21 production and ICOS upregulation in antigen-stimulated pTfh. Using these criteria, we observed higher CSP-specific pTfh in P subjects throughout the study, indicating a critical role of functional pTfh cells for protection against Plasmodium infection. IL-21 is the signature cytokine of Tfh cells and is required for optimal B cell function (Crotty, 2011; Linterman and Vinuesa, 2010; Vogelzang et al., 2008; Bryant et al., 2007; Pallikkuth and Pahwa, 2013). Likewise, ICOS–ICOSL interactions are known to be important for Tfh–B cell collaboration and also for IL-21 gene transcription in Tfh cells through c-Maf (Bossaller et al., 2006; Bauquet et al., 2009). These results add to the growing body of evidence pointing to the importance of IL-21 (Schultz et al., 2016; Spensieri et al., 2016; de Armas et al., 2017b) and ICOS (Bentebibel et al., 2016; Bentebibel et al., 2013; Herati et al., 2014; Havenar-Daughton et al., 2016) in circulating CD4 T cells or CSP-specific pTfh as biomarkers of vaccine responses. In the data integration analysis, neither the non-pTfh cells nor IFNγ+ CSP-specific CD4 and pTfh responses were identified as variables that were associated with protection or regimen difference, reaffirming the central role of antigen-specific pTfh cells in the CD4 T cell compartment in the response to vaccination. The actual timing, magnitude and duration of the pTfh response that needs to be elicited in order to generate qualitatively superior B cell responses for improved protection in the DFD regimen will require further investigations.

To understand the nature of the B cell response to the vaccine, we examined changes in specific subsets in the context of protection and regimen. The development of strong, functionally competent CSP-specific memory B cells after the second dose in protected subjects suggests the development of highly Ag-experienced functional memory B cells following the early pTfh response induced by vaccination. Development of a CSP-specific memory B cell compartment is in line with previous studies on antibody affinity, B cell somatic hypermutation, and antibody function, and suggests that affinity maturation is altered to some extent in the DFD regimen (Regules et al., 2016; Chaudhury et al., 2017). The stronger vaccine-induced memory B cell responses elicited towards PF-16 (the C-terminus of the CSP protein) over R32LR (the central repeat region) may have played a role in protection, as this region is implicated in the initial entry of the sporozoites into hepatocytes (Ramasamy, 1998). In our study, we found persistence of the vaccine-induced CSP-specific memory B cells up to 159 days post-challenge, the last time point for analysis. In a previous study, Pepper and colleagues reported persistence of Plasmodium-specific memory B cell populations that had been induced by protein immunization up to 340 days post-infection (Krishnamurty et al., 2016). Longer follow-up studies are needed to understand whether the vaccine-induced persistence of pTfh responses favors this B cell response in the DFD regimen. Interestingly, aMBC were also increased in the DFD regimen, compared to the STD regimen, at T5 and T6. These cells, originally described as an exhausted subset of memory B cells in HIV infection (Moir and Fauci, 2009; Moir et al., 2008), have been found in the circulation of Plasmodium-infected individuals from endemic countries (Ly and Hansen, 2019). A role for aMBC in malaria immunity has been suggested on the basis of the accumulation of this sub-population in situations of parasitemia or shorter exposure history (Weiss et al., 2009; Changrob et al., 2018) in children and adults from malaria endemic areas (Weiss et al., 2009; Changrob et al., 2018; Portugal et al., 2015); importantly, aMBC were maintained in situations of persistent parasite exposure (Ayieko et al., 2013) with a decline over 12 months in the absence of transmission. The functional significance of vaccine-induced aMBC expansion and the role of these cells in the development of immunity to malaria needs further investigation.

A major objective of the present study was to determine the mechanism behind the improved protection in the DFD vaccination regimen as compared to the STD regimen. As both the STD and DFD groups received the same regimen during the first two doses, differences between the study arms were expected only after the second dose, when the regimens split into either a reduced third dose at 7 months in the DFD group or a full third dose one month after the second dose in the STD group. To explore how the DFD regimen enhances efficacy, we used machine-learning tools and made individualized predictions of protection on the basis of early immune responses (pre-dose 3) alone. Using this analysis, we were able to identify a group of non-protected participants in the STD regimen who showed a promising immune response after doses 1 and 2, but lost this response after the third dose. These data suggest that dose 3 in the STD dose schedule has an adverse effect on an otherwise promising immune response generated by the first two doses. This effect could be caused by the Ag or adjuvant concentration of the full third dose, or by the one-month spacing between dose 2 and dose 3, which may hinder the selection of high-affinity B and T cell clones, either through overstimulation and anergy, or through weak selection pressure resulting from high Ag availability (Alexander-Miller et al., 1996).

Our data on ex vivo frequencies of dead cells did not differ significantly between the DFD and STD regimens immediately after (day 6) of the third dose (data not shown), and refute the possibility of a higher rate of cell death in the STD regimen. Our results suggest that NP subjects in the STD regimen are a mix of two classes of subjects, true weak responders and strong responders that aren’t protected. This mixed population may explain why it has been difficult to find correlates of protection in RTS,S studies (Ockenhouse et al., 2015). By contrast, in the new DFD regimen, NP subjects are almost entirely of one class — weak responders. On the basis of the overall findings, we suggest that the early Tfh response, induced by the initial two vaccine doses, results in the formation of a strong high-affinity memory B cell pool that is specific to CSP antigen; in the DFD, this leads to the expansion and differentiation of the pre-formed memory B cells to Ab-secreting cells. By contrast, in the STD vaccine regimen, early administration of the booster dose was detrimental to the expansion and differentiation of pre-formed memory B cells. Previous reports found an association of CSP-specific IL-2⁺, TNF or IFNg⁺ CD4 T cells or Th1 responses with vaccine responses (Kester et al., 2009; Lumsden et al., 2011). These studies did not examine CSP-specific pTfh within the memory CD4 T cell compartment, and most probably included both pTfh and non-pTfh cells in their analysis. Our data show that within the Ag-specific CD4 T cell compartment, pTfh cells but not non-pTfh show a kinetic and functional response to the malaria vaccine.

It should be noted that our study had limitations. Only a small number of participants (4/30) became infected in the DFD regimen, precluding comparisons of infected and protected subjects within each study regimen. We also did not examine CSP-specific pTfh for their Th1 versus Th2 phenotype or for response to individual CSP peptides in order to fine-map the pTfh responses. In a recent influenza vaccine study, we found that vaccine non-responders were polarized towards an inflammatory Th1/Th17 phenotype with predominant production of inflammatory cytokine TNF and Tfh antagonistic cytokine IL-2, while in responders, pTfh cells showed a Th2 phenotype with ICOS upregulation and IL-21 production (Pallikkuth et al., 2019). Another study has documented a negative impact of CXCR3⁺, a marker of Th1 type pTfh, on antibody quantity and quality in a vaccine trial involving RTS,S/AS01B (Bowyer et al., 2018). More detailed characterization of the functional and phenotypic heterogeneity of pTfh in future malaria vaccine studies may be informative. Further analyses are needed to ascertain the relationships of the immune parameters investigated herein with the magnitude and breadth of the Ab responses.

We conclude that delaying and reducing the third vaccine dose is advantageous for developing a protective immune response. This is highlighted particularly in those individuals that elicited promising responses after the first two doses, which then seemed to be disrupted when the third dose of RTS,S/AS01 was administered at the standard concentration one month after the second dose. We recognize that the CHMI studies of RTS,S-vaccinated malaria-naive adults represent a controlled setting for the study of immune response in relation to vaccine-induced protection. Whether the DFD regimen can be translated into the field with beneficial effects remains to be seen. The long interval between the second and third doses may be challenging in the face of overwhelming exposure to mosquitoes that can inoculate sporozoites into the host in this period, thereby affecting the development of immunity. However, the amount of CSP delivered via natural infection is much lower than the amount of CSP in RTS,S/AS01 and, thus, it is unlikely that natural infection would disrupt the development of an otherwise protective immune response. Recently, it was shown that children who responded well to RTS,S/AS01 vaccination had increased baseline frequencies of antibody-secreting and Tfh cells (Hill et al., 2020). Nevertheless, emerging data also suggests that malaria infection may induce memory Tfh cells that have impaired B cell helper function, and may inhibit differentiation to fully functional Tfh cells, thus resulting in germinal center dysfunction and suboptimal antibody responses (Hansen et al., 2017). Last, our data indicate the generation of strong CSP-specific pTfh responses that persist even after 159 days post-challenge, suggesting that CSP-specific pTfh could serve as potential biomarkers for vaccine efficacy. Monitoring CSP-specific pTfh should be considered in future malaria vaccine trials in clinical settings or field studies.

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, 4 and 5.

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Author details

1. Suresh Pallikkuth

   Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

2. Sidhartha Chaudhury

   Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, United States

   Present address

   Center for Enabling Capabilities, Walter Reed Army Institute of Research, Silver Spring, United States

   Contribution

   Data curation, Software, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

3. Pinyi Lu

   1. Biotechnology HPC Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, United States
   2. Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, United States

   Contribution

   Software, Formal analysis

   Competing interests

   No competing interests declared

4. Li Pan

   Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States

   Contribution

   Software, Formal analysis

   Competing interests

   No competing interests declared

5. Erik Jongert

   GSK Vaccine, Rixensart, Belgium

   Contribution

   Conceptualization, Methodology, Writing - review and editing

   Competing interests

   is an employee of GSK, and owns shares of GSK

6. Ulrike Wille-Reece

   PATH’s Malaria Vaccine Initiative, Washington DC, United States

   Contribution

   Conceptualization, Resources, Supervision, Methodology, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

7. Savita Pahwa

   Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Methodology, lab facilities, technical support, writing, review and editing

   For correspondence

   spahwa@med.miami.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4470-4216

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