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The Journal of Immunology, 1999, 162: 7309-7314.
Copyright © 1999 by The American Association of Immunologists

Absolute Requirement for an Active Immune Response Involving B Cells and Th Cells in Immunity to Plasmodium yoelii Passively Acquired with Antibodies to the 19-kDa Carboxyl-Terminal Fragment of Merozoite Surface Protein-11

Chakrit Hirunpetcharat*, Peter Vukovic*, Xue Qin Liu*, David C. Kaslow{dagger}, Louis H. Miller{dagger} and Michael F. Good2,*

* Queensland Institute of Medical Research, Brisbane, Australia; and {dagger} Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Vaccination of mice with the leading malaria vaccine candidate homologue, the 19-kDa carboxyl terminus of merozoite surface protein-1 (MSP119), results in sterile immunity to Plasmodium yoelii, with no parasites detected in blood. Although such immunity depends upon high titer Abs at challenge, high doses of immune sera transferred into naive mice reduce parasitemia (and protect from death) but do not result in a similar degree of protection (with most mice experiencing high peak parasitemias); this finding suggests that ongoing parasite-specific immune responses postchallenge are essential. We analyzed this postchallenge response by transferring Abs into manipulated but malaria-naive mice and observed that Abs cannot protect SCID, nude, CD4+ T cell-depleted, or B cell knockout mice, with all mice dying. Thus, in addition to the Abs that develop following MSP119 vaccination, a continuing active immune response postchallenge is required for protection. MSP119-specific Abs can adoptively transfer protection to strains of mice that are not protected following vaccination with MSP119, suggesting that the Ags targeted by the immune response postchallenge include Ags apart from MSP119. These data have important implications for the development of a human malaria vaccine.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Although immunity to malaria can be induced by repeated exposure to malaria parasites, the quest to develop a subunit vaccine has not yet been successful (1). A few leading candidates are currently being tested in animal systems. The 19-kDa carboxyl-terminal fragment of the merozoite surface protein-1 (MSP119)3 is the most promising (2, 3, 4, 5, 6, 7, 8). Mice immunized with MSP119 from Plasmodium yoelii are completely protected, with parasites never detected in the peripheral blood (7). Control animals die within 8 days of challenge. However, the mechanism of protection is not well understood.

Studies have implicated Abs in particular in MSP119-induced immunity (7). However, serum from MSP119-immunized mice can adoptively transfer only partial protection to naive recipients (6); all mice developed patent infection postchallenge, with mice ultimately curing if the amount of transferred Ab is sufficient. The ability of these mice to eradicate parasites must be due to factors other than the transferred Abs per se, because the parasites are being cleared when the level of Ab is less than the level prechallenge. This finding, when taken together with the observation that a depletion of CD4+ T cells from MSP119-immunized mice can abrogate immunity (4, 7), suggests that T cells are required for immunity postchallenge. To address the nature of the postchallenge immune response, we compared the ability of MSP119 immune serum to transfer immunity to normal, SCID, nude, CD4+ T cell-depleted, and B cell-deficient (µMT) mice (10, 11).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice and parasites

We used 6- to 8-wk-old C3H/HeJ, BALB/c, BALB/c nude (nu/nu), SCID, C57BL/6 (B6), and µ-chain knockout (KO) mice (10, 11). The KO mice, which were kindly provided by Barbara Fazekas de St Groth, were originally obtained from The Jackson Laboratory (Bar Harbor, ME) and were backcrossed to the B6 background for >=10 generations. These mice have neither B cells nor Ab. P. yoelii YM (lethal) (12) was used.

Recombinant MSP119

MSP119 of P. yoelii was produced in Saccharomyces cerevisiae (yMSP119) as described previously (6).

Preparation of MSP119 immune sera

BALB/c mice were immunized with MSP119 using a parenteral immunization protocol described previously as protocol A (7).

Ab depletion

Serum was depleted of Ab by passage over an immobilized protein A agarose column (Pierce, Rockford, IL) according to the manufacturer’s instructions. Analysis of immune serum from mice optimally vaccinated with MSP119 (7) revealed a 150-fold reduction in MSP119-specific titer following treatment.

Passive transfer study

Mice were injected i.p. with 0.5 ml of MSP119 immune serum at days -1, 0, and 1, relative to the day of challenge infection (resulting in a titer of ~2 x 106 in the recipient). Mice were challenged i.v. with 104 P. yoelii YM parasitized RBCs (pRBCs) on day 0. Parasitemias were monitored as described previously (7).

In vivo CD4+ T cell depletion

Mice were depleted of CD4+ T cells by three daily treatments with 1 mg of rat anti-CD4 (GK1.5) mAb before challenge with parasite (7).

Ab assay

An MSP119-specific ELISA was performed as described previously (7).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
MSP119-specific passive immunity in normal mice

First, we confirmed that three injections each of 0.5 ml of immune serum around the time of challenge (resulting in an immediate titer of ~2 x 106 in the recipient) can delay patency of infection and ultimately enable normal immunocompetent mice to resolve their infection after a peak parasitemia of 1–44% (Fig. 1Go). Although the serum donors themselves were not challenged before taking serum, other mice similarly immunized were challenged and were solidly immune (parasites not detected postchallenge), with titers at the time of challenge ranging from 0.5 x 106 to 6 x 106. Immune sera passively transfer protection in a dose-dependent manner. Normal mice given three doses of 0.5 ml of pooled sera were protected after a patent infection, whereas two of three animals given three doses of 0.25 ml of sera showed a delayed patency before suc-cumbing; mice given three doses of 0.1 ml of sera or three doses of PBS before challenge were not protected at all. Membrane filtration of immune sera, excluding molecules of >30 kDa, removed all protective effect from the serum, excluding the possibility that Ag (19 kDa) may be present in the serum and responsible for protection (data not shown). Furthermore, depletion of Ig from immune serum by passage over a protein A column (Materials and Methods) completely abolished the ability of the serum to protect C3H recipients (data not shown).



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  		FIGURE 1. Protection and Ab response induced following passive transfer of MSP119 immune serum into mice followed by challenge infection. B6 (A) and BALB/c (B) mice were administered three i.p. daily injections of 0.5 ml of NMS or MSP119 immune serum on days -1, 0, and 1, relative to the day of parasite challenge. Mice were challenged i.v. with 104 P. yoelii YM pRBCs on day 0. Sera were collected every 2 days and assayed for Abs to MSP119 by ELISA. The panels in B refer to individual mice.

 
We also show that the titer of MSP119-specific Abs falls during the ascent of parasitemia, which is consistent with the passively transferred Abs being adsorbed by merozoites (Fig. 1GoB). To exclude the possibility that the fall in Ab may be due to simple physiological turnover, we conducted experiments in which mice received either MSP119-specific immune serum or serum from mice immunized with an irrelevant Ab specific for peptide 145 of the M protein of group A streptococcus (13). Following infection, we observed a fall in MSP119-specific titer from 106 to ~103 in mice that received these Abs and that were challenged, coinciding with the increase in parasitemia. Unchallenged mice had a very small drop (to 3 x 105) over the course of the experiment. There was no change in the titer of p145-specific Abs over the course of the experiment in either the challenged or nonchallenged group.

Parasitemia subsequently falls in the passively immunized mice at a time when the titer of MSP119-specific Abs is low, which is suggestive of an active immune response. Furthermore, after clearance of parasites, the level of MSP119-specific Abs subsequently rises again, which is consistent with active Ab production.

Passively transferred MSP119-specific Abs cannot eliminate parasites

To demonstrate that the ultimate clearance of the parasite was not due to the transferred Abs per se, we transferred immune serum to SCID mice. Although these mice were able to control infection for <=8 days, they developed patent infection that did not resolve (Fig. 2Go). To exclude the possibility that parasites were not sequestered away from Ab for the 8-day prepatent period, we transferred blood from infected mice to naive reporter mice at days 2, 4, 6, and 8 postchallenge and observed that reporter mice developed malaria infection in all cases (Fig. 2GoC). Thus, an active immune response was required to clear parasites from mice that were passively administered MSP119-specific Abs.



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  		FIGURE 2. Subpatent parasitemias in mice that were passively transferred MSP119 immune serum. SCID mice were administered three daily 0.5-ml injections of NMS (A) or MSP119 immune serum (B and C) on days -1, 0, and 1, relative to the day of parasite challenge. Mice were challenged i.v. with 104 P. yoelii YM pRBCs on day 0. Blood was collected every 2 days after challenge from the mice in group C and transferred into naive BALB/c mice; parasitemias were examined (small boxes as indicated by arrows).

 
Requirement for T cells and Th cells

To determine a requirement for naive T cells at the effector stage, serum from MSP119-immunized mice was transferred into normal and athymic (nu/nu) naive BALB/c mice (Fig. 3Go, A–D). Postchallenge, athymic recipients of MSP119-specific Abs or normal mouse serum (NMS) developed high parasitemia and died. We assessed the contribution of CD4+ T cells by depleting normal B6 mice with either GK1.5 (anti-CD4) Abs or normal rat Ig (NRIg) before the administration of MSP119-specific serum and challenge (Fig. 3Go, E and F). GK1.5 treatment, as assessed by FACS analysis, destroyed 98.8% of splenic CD4+ T cells in nonchallenged littermates. Postchallenge, we observed that the NRIg group survived after a patent parasitemia of 2–24%, whereas all mice in the GK1.5-treated group died. Thus, naive CD4+ T cells are required for immunity in mice administered MSP119-specific Abs. Next, we performed passive transfer studies in B cell-deficient (µMT) mice (which have T cells that are capable of reacting by proliferation to MSP119 following vaccination (7)). Although patent parasitemia was delayed in the group that received anti-MSP119 immune serum, these mice were unable to control their parasitemias (Fig. 4Go).



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  		FIGURE 3. Requirement of CD4+ T cells for recovery from infection. Normal BALB/c, BALB/c nude, and B6 mice were administered three daily i.p. injections of 0.5 ml of NMS (A and C) or MSP119 immune serum (B and D–F) on days -1, 0, and 1, relative to the day of parasite challenge. B6 mice were treated with NRIg (E) or anti-CD4 mAb (F) as described in Materials and Methods. Mice were challenged i.v. with 104 P. yoelii YM pRBCs on day 0.

 


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  		FIGURE 4. Passive transfer of MSP119 immune serum into B cell-deficient mice. B cell KO mice were administered three daily i.p. injections of 0.5 ml of NMS (A) or MSP119 immune serum (B) on days -1, 0, and 1, relative to the day of parasite challenge. Mice were challenged i.v. with 104 P. yoelii YM pRBCs on day 0.

 
Ability of MSP119-specific Abs to transfer protection to strains of mice not protected following MSP119 vaccination

The above data strongly suggest that an active immune response is required postinfection for MSP119 vaccination to be effective. The stimulus for that immune response must obviously be the parasite, not the vaccine. The target Ag or Ags within the parasite are not known. If MSP119 itself was the principal target, then it may be expected that strains of mice that were poor responders to MSP119 would not be protected by adoptively transferred Abs. To address this issue, we transferred Abs into three strains of normal immunocompetent mice (C57BL/10 (H-2b), B10.BR (H-2k), and B10.D2 (H-2d)) and subsequently challenged these mice with P. yoelii. We have shown previously that B10 mice are strongly protected following GST-MSP119 vaccination, but that B10.BR mice are not protected at all (6). The ability of MSP119 to protectively immunize B10.D2 mice has not been ascertained. As shown in Fig. 5Go however, all three strains of mice were equally protected by MSP119-specific Abs, with peak parasitemias of <40% in all animals. Control mice that received NMS instead of MSP119-specific Abs either died or suffered a peak parasitemia of between 60% and 80% postchallenge.



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  		FIGURE 5. Passive transfer of MSP119 immune serum or NMS into different strains of H-2 congenic mouse strains (as indicated). Mice received three daily i.p. injections of 0.5 ml of serum on days -1, 0, and 1, relative to the day of parasite challenge. Mice were challenged i.v. with 104 P. yoelii YM pRBCs on day 0.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results presented here show for the first time that an active immune response postchallenge is required for protection against malaria even if protective Abs are present prechallenge at high titer. It is important to note that this active postchallenge immune response is not a classical boosting response. Boosting implies an augmentation of the numbers of T and B cells initially induced by the vaccine itself following parasite challenge. The animals challenged in this study were naive with respect to the presence of vaccine-specific T and B cells. Rather, the immune response required postchallenge is a naive immune response targeting the parasite per se. Our system of passive transfer is clearly different from that in which animals are actively vaccinated. In that situation, classical boosting of the vaccine-induced immune response is likely to be very important. However, such boosting would significantly increase the titer of the vaccine-specific Abs only if the animal was able to respond to the vaccine Ag as present in the native parasite. We know from a number of malaria studies that this requirement cannot always be relied upon to occur (14); thus, such animals following active vaccination may be very similar to the animals in our system that adoptively received MSP119-specific Abs. Thus, although classical boosting of a vaccine-induced immune response will be important, it may not always occur; in such situations, and perhaps in all situations, our data argue that an additional immune response is required.

The mechanism by which the passively transferred Abs delay the patency of the infection was not studied here. However, our data strongly suggest that during infection, specific Abs, but not Abs of an irrelevant specificity, are consumed. Abs may function by blocking the processing of the larger mature MSP1 protein on the merozoite surface (15) or may simply sterically hinder the merozoite invasion of erythrocytes.

The data presented here are particularly encouraging for the likely efficacy of subunit malaria vaccines. Although we have shown that an active de novo immune response postchallenge is required for protection as well as the vaccine-induced Ab response prechallenge, the data also show that mice that cannot be protected following vaccination with a particular subunit preparation can be passively protected by adoptively transferred Abs. B10.BR mice are not protected following vaccination with GST-MSP119 (6). The reasons for this are not clear, but may relate to the titer of Ab induced by vaccination or to other factors such as the fine specificity of the Ab response. However, these factors may be overcome, for example by conjugation to a different carrier protein, which may provide more T cell help. It would then be expected that these mice would be protected postchallenge, because the active immune response postchallenge is not restricted to MSP119 per se but to other, possibly multiple, parasite Ags. If this was not the case, B10.BR mice would not be expected to be protected following adoptive transfer of MSP119-specific Abs; however, these mice were in fact protected as well as B10 mice (Fig. 5Go) (a strain that is strongly protected following vaccination) (6). If the mechanism of protection induced by other merozoite surface proteins, for example apical membrane Ag-1, is similar to that mediated by MSP119, then this has obvious and important implications for designing a human malaria vaccine, particularly small subunit vaccines based on merozoite surface proteins. If Ab is the principal mechanism of protection, then provided that a satisfactory Ab response is induced by vaccination, it is likely that the Ab response required postchallenge will not be restricted to the small subunit Ag, but will involve other proteins, thus increasing the likelihood of protection.

Our data provide an explanation as to why immunized mice can be solidly protected (no patent parasitemia), whereas normal mice passively given Abs develop a patent infection before cure. An active immune response postchallenge is critical for protection. The nature of the immune response could be humoral or cellular (or both). Infection of normal mice that have passively received anti-MSP119 Abs would result in a slower primary antiparasite immune response, which would take time to achieve protective levels. Meanwhile, the passively transferred Abs are being consumed; until the active response is sufficient, parasitemia increases. In contrast, vaccinated mice will have a rapid secondary immune response postchallenge (16).

The data in this paper also raise the possibility that anti-MSP119-specific Abs could be used in the treatment of clinical malaria. In the experiments described here, mice were challenged posttransfer. However, we have shown that adoptive transfer of serum postchallenge can also temporarily reduce parasitemia (our unpublished data). Such Abs might be considered as adjunct therapy to be given in conjunction with chemotherapeutic agents in cases in which the efficacy of the chemotherapy might be in doubt due to the prevalence of drug resistance.


   Acknowledgments
 
We thank Anne Kelso, David Pombo, Allan Saul, and Denise Doolan for their significant input into these studies and critical review of the manuscript.


   Footnotes
 
1 This work was supported by United Nations Development Program/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases, The National Health and Medical Research Council (Australia), The Cooperative Research Centre for Vaccine Technology, and the Australian Centre for International and Tropical Health and Nutrition. Back

2 Address correspondence and reprint requests to Dr. Michael F. Good, Queensland Institute of Medical Research, P.O. Royal Brisbane Hospital, Brisbane 4029, Australia. E-mail address: Back

3 Abbreviations used in this paper: MSP1, merozoite surface protein-1; B6, C57BL/6; KO, knockout; NRIg, normal rat Ig; NMS, normal mouse serum; pRBC, parasitized RBC. Back

Received for publication July 28, 1998. Accepted for publication March 11, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Good, M. F., D. C. Kaslow, L. H. Miller. 1998. Pathways and strategies for developing a malaria blood-stage vaccine. Annu. Rev. Immunol 16:57.[Medline]
  2. Holder, A. A., R. R. Freeman. 1981. Immunization against blood-stage rodent malaria using purified parasite antigens. Nature 294:361.[Medline]
  3. Daly, T. M., C. A. Long. 1993. A recombinant 15-kilodalton carboxyl-terminal fragment of Plasmodium yoelii 17XL merozoite surface protein 1 produces a protective immune response in mice. Infect. Immun. 61:2462.[Abstract/Free Full Text]
  4. Daly, T. M., C. A. Long. 1995. Humoral response to a carboxyl-terminal region of the merozoite surface protein-1 plays a predominant role in controlling blood-stage infection in rodent malaria. J. Immunol. 155:236.[Abstract]
  5. Ling, I. T., S. A. Ogun, A. A. Holder. 1994. Immunization against malaria with a recombinant protein. Parasite Immunol. 16:63.[Medline]
  6. Tian, J. H., L. H. Miller, D. C. Kaslow, J. Ahlers, M. F. Good, D. W. Alling, J. A. Berzofsky, S. Kumar. 1996. Genetic regulation of protective immune response in congenic strains of mice vaccinated with a subunit malaria vaccine. J. Immunol. 157:1176.[Abstract]
  7. Hirunpetcharat, C., J. H. Tian, D. C. Kaslow, N. van Rooijen, S. Kumar, J. A. Berzofsky, L. H. Miller, M. F. Good. 1997. Complete protective immunity induced in mice by immunization with 19-kilodalton carboxyl-terminal fragment of the merozoite surface protein-1 (MSP119) of Plasmodium yoelii expressed in Saccharomyces cerevisiae: correlation of protection with antigen-specific antibody titer, but not with effector CD4+ T cells. J. Immunol. 159:3400.[Abstract]
  8. Kumar, S., A. Yavada, D. B. Keister, J. H. Tian, M. Ohl, K. A. Perdue-Greenfield, L. H. Miller, D. C. Kaslow. 1995. Immunogenicity and in vivo efficacy of recombinant Plasmodium falciparum merozoite surface protein-1 in Aotus monkeys. Mol. Med. 1:325.[Medline]
  9. Rockett, K. A., M. M. Awburn, W. B. Cowden, I. A. Clark. 1991. Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect. Immun. 59:3280.[Abstract/Free Full Text]
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  11. Epstein, M. M., F. Di Rosa, D. Jankovic, A. Sher, P. Matzinger. 1995. Successful T cell priming in B cell-deficient mice. J. Exp. Med. 182:915.[Abstract/Free Full Text]
  12. Lewis, A. P.. 1989. Cloning and analysis of the gene encoding the 230-kilodalton merozoite surface antigen of Plasmodium yoelii. Mol. Biochem. Parasitol. 36:271.[Medline]
  13. Pruksakorn, S., A. Galbraith, R. A. Houghten, M. F. Good. 1992. Conserved T and B cell epitopes on the M protein of group A streptococci: induction of bactericidal antibodies. J. Immunol. 149:2729.[Abstract]
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Merozoite Surface Protein 1-Specific Immune Response Is Protective against Exoerythrocytic Forms of Plasmodium yoelii
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Protective Immune Responses to the 42-Kilodalton (kDa) Region of Plasmodium yoelii Merozoite Surface Protein 1 Are Induced by the C-Terminal 19-kDa Region but Not by the Adjacent 33-kDa Region
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J. Wipasa, H. Xu, A. Stowers, and M. F. Good
Apoptotic Deletion of Th Cells Specific for the 19-kDa Carboxyl-Terminal Fragment of Merozoite Surface Protein 1 During Malaria Infection
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CD4+ T Cells Acting Independently of Antibody Contribute to Protective Immunity to Plasmodium chabaudi Infection After Apical Membrane Antigen 1 Immunization
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Immunoglobulin G3 Antibodies Specific for the 19-Kilodalton Carboxyl-Terminal Fragment of Plasmodium yoelii Merozoite Surface Protein 1 Transfer Protection to Mice Deficient in Fc-gamma RI Receptors
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