Re-investigation of the circumsporozoite protein-based induction of sterile immunity against Plasmodium berghei infection

doi:10.1016/0264-410X(95)00175-Z

Vaccine

Volume 14, Issue 8, June 1996, Pages 828-836

https://doi.org/10.1016/0264-410X(95)00175-Z Get rights and content

Abstract

Although the circumsporozoite protein (CSP) of the malaria parasite is the most immunologically characterized protein, the goal of using this protein in an effective vaccine has not yet been realized. Monoclonal antibody against the repetitive immunodominant B-epitope of the CSP can protect mice from malaria, but vaccines that induce antibody against this epitope do not consistently induce protection. Toward developing a rationale for a CSP-based effective vaccine, we have re-investigated the ability of anti-CSP repeat antibodies, as induced by different CSP vaccine formulations with several adjuvants, to confer sterile immunity against sporozoite challenge. Using Plasmodium berghei rodent malaria model and several CSP subunit vaccine constructs, we found that a formulation consisting of the P. berghei CSP repetitive epitope, (DPPPPNPN)₂ (CS), conjugated to BSA by carbodiimide, formulated in a block copolymer and detoxified lipopolysaccharide (RaLPS) adjuvant, was particularly promising. Mice were immunized and boosted with vaccines that contain varying malarial peptide-carrier ratios of 6:1 (CS₆-BSA), 55:1 (CS₅₅-BSA) and 170:1 (CS₁₇₀-BSA). Following immunization, the animals were challenged with live sporozoites. Two types of effects were observed in vaccinated mice. First, sterile immunity was induced in 100%, 50% and 29% of mice that were immunized with the CS₁₇₀-BSA, CS₅₅-BSA, and CS₆-BSA vaccine conjugates, respectively. The second effect of immunization was observed with the CS₁₇₀-BSA conjugate vaccine primed mice; a boost in IFA titers followed sporozoite challenge. In addition, we observed that IgG1 isotype titer against the surface of the sporozoite, as measured by IFA, and antibody avidity parallel sterile immunity. These findings reiterate the potential of the CSP as a malaria vaccine candidate antigen, and suggest that the induction of sterile immune responses depends on inducing antibody of the appropriate isotype, avidity and specificity.

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Cited by (21)

Modelling the roles of antibody titre and avidity in protection from Plasmodium falciparum malaria infection following RTS,S/AS01 vaccination
2020, Vaccine
Citation Excerpt :
Antibody avidity measured using inhibition ELISAs is a representation of the overall strength of interaction between antibodies and antigens in a complex, it takes into account the intrinsic affinity of antibodies to their specific epitopes and also valences of antibodies and any structural features of antibody binding confirmations [26–28]. High avidity antibodies have been shown to be important in the protection conferred by several viral and bacterial vaccines [29–33] but studies of antibody avidity responses following 012M RTS,S vaccination during field trials have provided conflicting evidence on the relationship between avidity and protection from infection thus far [34–37]. Here we re-analyse the immunological data from the delayed-fractional challenge trial using a biologically-motivated mathematical model of P. falciparum sporozoite inoculation [10].
Anti-circumsporozoite antibody titres have been established as an essential indicator for evaluating the immunogenicity and protective capacity of the RTS,S/AS01 malaria vaccine. However, a new delayed-fractional dose regime of the vaccine was recently shown to increase vaccine efficacy, from 62.5% (95% CI 29.4–80.1%) under the original dosing schedule to 86.7% (95% CI, 66.8–94.6%) without a corresponding increase in antibody titres. Here we reanalyse the antibody data from this challenge trial to determine whether IgG avidity may help to explain efficacy better than IgG titre alone by adapting a within-host mathematical model of sporozoite inoculation. We demonstrate that a model incorporating titre and avidity provides a substantially better fit to the data than titre alone. These results also suggest that in individuals with a high antibody titre response that also show high avidity (both metrics in the top tercile of observed values) delayed-fractional vaccination provided near perfect protection upon first challenge (98.2% [95% Credible Interval 91.6–99.7%]). This finding suggests that the quality of the vaccine induced antibody response is likely to be an important determinant in the development of highly efficacious pre-erythrocytic vaccines against malaria.
Irradiated sporozoite vaccination induces sex-specific immune responses and protection against malaria in mice
2019, Vaccine
Citation Excerpt :
Preclinical animal models have proven useful for studying vaccine efficacy and the immune response to malaria [14]. Little consideration, however, has been given to sex as a biological variable, with most studies either not reporting the sex of the animals or only using female animals [15–18]. In murine studies of malaria blood stage infection, females have reduced mortality, experience faster resolution of infection-associated anemia and weight loss, and mount a more robust immune response to infection (e.g. increased IFNƴ, IL-10, and Plasmodium specific IgG1 antibody production) than males [19].
In both preclinical animal studies and human clinical trials, adult females tend to develop greater adaptive immune responses than males following receipt of either viral or bacterial vaccines. While there is currently no approved malaria vaccine, several anti-sporozoite vaccines, including RTS,S/AS01 and attenuated sporozoite vaccines, are in development, but the impact of sex and age on their efficacy remains undefined. To examine sex differences in the efficacy of anti-sporozoite stage malaria vaccination, adult (10 weeks of age) or juvenile (11 days of age) male and female C3H mice were twice vaccinated with irradiated transgenic Plasmodium berghei sporozoites expressing the P. falciparum circumsporozoite (CSP) protein and 45 days post boost vaccination, mice were challenged with transgenic P. berghei via mosquito bite or intradermal challenge. Immunization with irradiated sporozoites resulted in greater protection against challenge in adult females, which was associated with greater anti-CSP antibody production and avidity, as well as greater hepatic, but not splenic, CD8⁺ T cell IFNƴ production in adult females than adult males. No sex differences in adaptive immune responses or protection were observed in mice vaccinated prior to puberty, suggesting a role for sex steroid hormones. Depletion of testosterone in males increased, whereas rescue of testosterone decreased, anti-CSP antibody production, the number of antigen-specific CD8⁺ T cells isolated from the liver, and protection following parasite challenge. Conversely, depletion of sex steroids in female mice did not alter vaccine-induced responses or protection following challenge. These data suggest that elevated testosterone concentrations in males reduce adaptive immunity and contribute to sex differences in malaria vaccine efficacy.
Molecular adjuvants for malaria DNA vaccines based on the modulation of host-cell apoptosis
2009, Vaccine
Citation Excerpt :
Following the discovery of CSP-specific cytotoxic effector T cells in the P. yoelii model [33], a significant effort was made to demonstrate an equivalent cell population after immunization with P. berghei-CSP-vaccines. Despite the identification of putative MHC-I epitopes on the P. berghei CS protein and the identification of irradiated sporozoite-induced CD8 effector cells in the liver that secrete NOS and IFN-γ [34], it appears that antibodies are the main effector molecules in this disease model [27,35] while CD8 T cells – at least in certain models of P. berghei – are linked to pathogenesis, not protection [36]. Studies designed to address this question, however, have been hampered by the parasites sensitivity to changes in the host's immune status.
Malaria represents a major global health problem but despite extensive efforts, no effective vaccine is available. Various vaccine candidates have been developed that provide protection in animal models, such as a gene gun-delivered DNA vaccine encoding the circumsporozoite protein (CSP) of Plasmodium berghei. A common shortcoming of most malaria vaccines is the requirement for multiple immunizations leaving room for improvement even for established vaccine candidates such as the CSP-DNA vaccine. In this study, we explored whether regulating apoptosis in DNA vaccine transfected host cells could accelerate the onset of protective immunity and provide significant protection after a single immunization. A pro-apoptotic gene (Bax) was used as a molecular adjuvant in an attempt to mimic the immunostimulatory apoptosis triggered by viral or virus-derived vaccines, while anti-apoptotic genes such as Bcl-XL may increase the life span of transfected cells thus prolonging antigen production. Surprisingly, co-delivery of either Bax or Bcl-XL greatly reduced CSP-DNA vaccine efficacy after a single immunization. Co-delivery of Bax for three immunizations still had a detrimental effect on protective immunity, while repeated co-delivery of Bcl-XL had no negative impact. The fine characterization of humoral and cellular immune response modulated by these two molecular adjuvants revealed a previously unknown effect, i.e., a shift in the Th-profile. These results demonstrate that pro- or anti-apoptotic molecules should not be used as molecular adjuvants without careful evaluation of the resulting immune response. This finding represents yet another example that strategies to enhance vaccine efficacy developed for other model systems such as viral diseases cannot easily be applied to any vaccine.
Malaria vaccines for travelers
2004, Travel Medicine and Infectious Disease
Peptide-based subunit vaccines against pre-erythrocytic stages of malaria parasites
2001, Molecular Immunology
Malaria currently ranks among the most prevalent infections in tropical and sub-tropical areas throughout the world with relatively high morbidity and mortality particularly in young children. The widespread occurrence and the increased incidence of malaria in many countries, caused by drug-resistant parasites (Plasmodium falciparum and P. vivax) and insecticide-resistant vectors (Anopheles mosquitoes), indicate the need to develop new methods of controlling this disease. Experimental vaccination with radiation-attenuated sporozoites can protect animals and humans against the disease, demonstrating the feasibility of developing an effective malaria vaccine. However, vaccines based on radiation-attenuated sporozoites are not feasible for large scale application due to lack of in vitro culture system. Therefore, the development of peptide-based subunit vaccines has been undertaken as an alternative approach. Synthetic peptides containing defined B- and T-cell epitopes of different antigens expressed in sporozoites and/or liver stages have been used as subunit vaccines in experimental animal models. They have been shown to be highly immunogenic and capable of inducing protective immunity mediated by antibodies, as well as CD4+ and CD8+ T-cells.
Prolonged expression of IFNγ induced by protective blood-stage immunization against Plasmodium yoelii malaria
1999, Vaccine
Mice vaccinated with whole blood-stage antigens of Plasmodium yoelii develop protective, antibody-mediated immune responses to homologous challenge infection. In this model the level of protection induced by whole parasite antigen vaccination is dependent on antibody isotype, which can be influenced by adjuvant formulations. In this study the ability adjuvant formulations to affect cytokine production and protection against P. yoelii blood-stage infection was investigated. Survival of mice in groups vaccinated with P. yoelii antigens in an aqueous mix of copolymer P1005+RaLPS was 100%. Mice vaccinated with either P. yoelii antigens alone or combined with a water-in-oil emulsion of copolymer P1005+RaLPS demonstrated 83 or 50% survival, respectively. The fully protective aqueous vaccine group produced higher levels of interferon gamma (IFNγ) and interleukin 4 (IL-4) than the water-in-oil vaccine group following a live parasite challenge infection. Furthermore, mice vaccinated with the aqueous vaccine displayed prolonged IFNγ and IL-4 response as compared to mice that received the same antigens without adjuvants. These data support the hypothesis that both the Th1 cytokine IFNγ, and the Th2 cytokine IL-4 are modulated by the vaccine vehicle and adjuvant used for vaccination, thus possibly affecting expression of protective immune responses. However, it is the long-lasting IFNγ response following blood-stage P. yoelii parasite challenge that is associated with enhanced survival.

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Vaccine

Abstract

References (27)

Rationale for the development of an engineered sporozoite malaria vaccine

Adv. Immunol.

Adjuvant activity of nonionic block copolymers. IV. Effect of molecular weight and formulation on titer and isotype of antibody

Vaccine

Induction with a synthetic peptide of antibodies to HLA class I C-terminal intracytoplasmic region

Mol. Immunol.

Adjuvant activity of nonionic block copolymers V. Modulation of antibody isotype by lipopolysaccharides Lipid A and precursors

Vaccine

Use of adjuvant containing mycobacterial cell-wall skeleton, monophosphoryl lipid A, and squalane in malaria circumsporozoite protein vaccine

Lancet

Synthetic peptides as antigens: pitfalls of conjugation methods

J. Immunol. Meth.

Incorporation of T and B epitopes of the circumsporozoite protein in a chemically defined synthetic vaccine against malaria

J. Exp. Med.

In vivo testing of subunit vaccine against malaria sporozoites using a rodent system

Efficacy of murine malaria sporozoite vaccine: Implications for human vaccine development

Science

Synthetic peptide vaccine confers protection against murine malaria

J. Exp. Med.

Studies on the adjuvant activity of nonionic block polymer surfactants. I. The role of hydrophile-lipophile balance

J. Immunol.

Glycolipids in the pathogenesis of tuberculosis: studies on the relationship between the physiochemical properties and biologic activities of synthetic analogs of trehalose 6-6′ dimycolate

The adjuvant activity of nonionic block polymer surfactants. III. Characterization of selected biologically active surfaces

Scand. J. Immunol.

Cited by (21)

Modelling the roles of antibody titre and avidity in protection from Plasmodium falciparum malaria infection following RTS,S/AS01 vaccination

Irradiated sporozoite vaccination induces sex-specific immune responses and protection against malaria in mice

Molecular adjuvants for malaria DNA vaccines based on the modulation of host-cell apoptosis

Malaria vaccines for travelers

Peptide-based subunit vaccines against pre-erythrocytic stages of malaria parasites

Prolonged expression of IFNγ induced by protective blood-stage immunization against Plasmodium yoelii malaria

PaperRe-investigation of the circumsporozoite protein-based induction of sterile immunity against Plasmodium berghei infection

Abstract

Adv. Immunol.

Vaccine

Mol. Immunol.

Vaccine

Lancet

J. Immunol. Meth.

Incorporation of T and B epitopes of the circumsporozoite protein in a chemically defined synthetic vaccine against malaria

J. Exp. Med.

In vivo testing of subunit vaccine against malaria sporozoites using a rodent system

Efficacy of murine malaria sporozoite vaccine: Implications for human vaccine development

Science

Synthetic peptide vaccine confers protection against murine malaria

J. Exp. Med.

Studies on the adjuvant activity of nonionic block polymer surfactants. I. The role of hydrophile-lipophile balance

J. Immunol.

Glycolipids in the pathogenesis of tuberculosis: studies on the relationship between the physiochemical properties and biologic activities of synthetic analogs of trehalose 6-6′ dimycolate

The adjuvant activity of nonionic block polymer surfactants. III. Characterization of selected biologically active surfaces

Scand. J. Immunol.

Paper
Re-investigation of the circumsporozoite protein-based induction of sterile immunity against Plasmodium berghei infection