The seeds for development of a malaria vaccine at NYU were planted in the early 1960s but the groundwork had been prepared long before. Many scientists and physicians had spent World War II working on malaria and malaria control projects and then continued with malaria studies when they returned to academic life in the United States. Harry Most had been involved in the development of chloroquine as an anti-malarial drug while with the U.S. Army, after which he returned to the United States to become Chairman of the Department of Preventive Medicine at NYU School of Medicine. During the early 1960s, Dr. Most served as Chairman of the Armed Forces Epidemiological Board and Director of its Commission on Malaria. With the financial support of this Board, he initiated a project at NYU on the biology of malaria. Over the next decade, the complete life cycle of two rodent malaria parasites, Plasmodium yoelii and Plasmodium berghei, were established as laboratory models by Jerome Vanderberg and Meir Yoeli, for whom the Plasmodium yoelii species was named (Vanderberg 1965). The P. berghei and yoelii rodent malaria models have provided the experimental basis for malaria vaccine research used throughout the world today.

In 1960 the Department was joined by an immunologist, Ruth Nussenzweig, and studies on the attenuated sporozoite vaccine studies were initiated in collaboration with Jerome Vanderberg. By immunizing mice with radiation attenuated sporozoites dissected from mosquito salivary glands, the group was successful in attaining almost total protection against subsequent challenge with viable sporozoites (Nussenzweig, Vanderberg et al. 1967). The fundamental characteristics of this protection were worked out, including its species-specificity, stage specificity (restricted to sporozoite challenge) and properties of the humoral immune response. It was noted that upon exposure to serum from immunized mice, an antibody-mediated precipitant reaction was formed around sporozoites in vitro, termed the circumsporozoite precipitation (CSP) reaction (Vanderberg, Nussenzweig et al. 1969) providing an in vitro assay for sporozoite specific immunity. Subsequent studies demonstrated that sporozoite motility was inhibited by serum from immunized mice (Vanderberg 1974) and anti-sporozoite antibodies were able to block sporozoite invasion and infectivity both in vitro (Hollingdale, Nardin et al. 1984; Stewart, Nawrot et al. 1986) and in vivo (Vanderberg and Frevert 2004). Subsequent studies in humans demonstrated that multiple exposures to the bites of irradiated P. falciparum or P. vivax infected mosquitoes elicited sterile immunity and complete protection against infection (Clyde, Most et al. 1973; Clyde 1990). Over the years, numerous groups have repeated these experiments and shown that immunization by exposure to bites of irradiated falciparum infected mosquitoes reproducibly elicits high levels of sterile immunity in humans (Herrington, Davis et al. 1991; Egan, Hoffman et al. 1993; Hoffman, Goh et al. 2002) providing the “gold standard” for development of vaccines targeting the pre-erythrocytic stages of the malaria parasite.

The sporozoite stage of the parasite however cannot be grown in culture and early attempts to produce large numbers of sporozoites by culture techniques proved to be impractical, although the technical and logistical problems of an attenuated vaccine have recently has been revisited (Luke and Hoffman 2003). During the late 1970s, the maturation of molecular biology as a scientific endeavor suggested an entirely new approach, namely the development of subunit malaria vaccines. At about this time, Victor Nussenzweig (of NYU's Dept. of Pathology) joined the studies and a team led by the Nussenzweigs began to characterize the sporozoite surface antigens against which the CSP antibody acted. The target of protective monoclonal and polyclonal antibodies derived from sporozoite immunized and protected hosts was defined by this group and found to be a major surface antigen termed the circumsporozoite (CS) protein (Potocnjak, Yoshida et al. 1980; Yoshida, Nussenzweig et al. 1980; Cochrane, Santoro et al. 1982; Nardin, Nussenzweig et al. 1982). Passive transfer of small amounts of repeat specifc MAB protected naïve recipients from sporozoite induced infection. Molecular biologists in the department used these protective MAB to clone the CS gene, initially from a simian parasite (Godson, Ellis et al. 1983; Ozaki, Svec et al. 1983) followed by CS genes of human and rodent species of Plasmodium (Ellis, Ozaki et al. 1983; Enea, Ellis et al. 1984; Arnot, Barnwell et al. 1985; Eichinger, Arnot et al. 1986). In honor of these accomplishments, the Department of Medical and Molecular Parasitology was established in 1984 with Ruth Nussenzweig as Chair. It remains the only Parasitology Department in a Medical School in the US. Through the work of Drs Nussenzweig, NYU holds the patent on CSP, and in 1989 licensed it non-exclusively to Glaxo Smith Kline, royalty free.

In more recent studies, cell biologist in the department have elucidated the function of the CS protein in targeting the parasite to the liver and in host cell invasion (Cerami, Frevert et al. 1992; Frevert, Sinnis et al. 1993; Sinnis, Clavijo et al. 1994) while molecular knock outs of the CS protein have defined it’s role in sporogenesis (Menard, Sultan et al. 1997; Thathy, Fujioka et al. 2002). The CS “knockout” parasites have also been used to construct hybrid rodent parasites that express falciparum repeat epitopes to allow analysis of functional anti-falciparum antibodies elicited during preclinical and clinical trials using the small rodent model (Persson, Oliveira et al. 2002).

Knowledge of the CS protein sequence provided peptide fragments and recombinant proteins for identification of the B and T cell epitopes recognized by sera and cells from sporozoite immunized and protected volunteers (Zavala, Cochrane et al. 1983; Zavala, Tam et al. 1985; Zavala, Tam et al. 1987; Nardin, Herrington et al. 1989; Moreno, Clavijo et al. 1993). The protective B cell epitope was contained in the central repeat region of the CS protein in each Plasmodium species and in the case of P. falciparum consisted of a highly conserved simple tetramer, NANP, repeated 30-40 times (Nussenzweig and Nussenzweig 1989). Extensive preclinical studies, using the murine malaria models established at NYU, led to NYU clinical trials of the first CS repeat peptide/protein conjugate vaccine to be tested in human volunteers that demonstrated protection of vaccinees against P. falciparum malaria (Zavala, Tam et al. 1985; Herrington, Clyde et al. 1987; Zavala, Tam et al. 1987).

Over the past two decades, there have been a number of Phase I trials of CS-based vaccines carried out by NYU using vaccine candidates comprised of synthetic peptides (Herrington, Clyde et al. 1987; Nardin, Oliveira et al. 2000; Nardin, Calvo-Calle et al. 2001), recombinant proteins (Herrington, Nardin et al. 1991) and virus-like particles (Nardin 2004; Oliveira GA 2005) and extensive preclinical studies of promising recombinant attenuated viruses in homologous and heterologous prime boost regimens (Miyahira, Garcia-Sastre et al. 1998; Rodrigues, Zavala et al. 1998). Additional vaccine candidates using similar delivery platforms, in addition to DNA vaccines and polyepitope vaccines that contain CS combined with antigens from the pre-erythrocytic and erythrocytic stage parasites, have been carried out by WRAIR, NMRI, Oxford University and other institutions (Ballou, Arevalo-Herrera et al. 2004).

Most recently, trials carried out by Glaxo Smith Kline and WRAIR using a CS protein virus-like particle have demonstrated 30-40% protection against infection and 56% reduction in clinical disease in 1-4 year old African children (Alonso, Sacarlal et al. 2004). These results, obtained in the target population that suffers over 1.1 million deaths each year from malaria infection (WHO 2002), are encouraging and demonstrate the feasibility of CS subunit vaccines. Continued efforts to optimize subunit vaccines by use of newly developed adjuvants (Gonzalez-Aseguinolaza, Van Kaer et al. 2002) and incorporation of blood stage in addition to other pre-erythrocytic stage antigens are expected to increase vaccine efficacy and help prevent the morbidity and mortality caused by Plasmodium parasites in over 300-400 million people worldwide.