Malaria sporozoites (SPZ) have evolved to migrate to the liver and invade liver cells (hepatocytes); essentially all SPZ that reach the bloodstream invade hepatocytes. The liver stage is an obligatory first phase of the parasite’s life cycle in humans. In the liver cell, the parasites multiply 50,000-60,000 fold, and the progeny, called merozoites, leave the liver and invade red blood cells, initiating the highly pathogenic blood stage of the parasite life cycle. After a week of unchecked growth in the blood, there are billions of parasites in the body causing the signs and symptoms of malaria, including high fever, headache, chills, muscle and joint aches, nausea and vomiting. The preceding liver stages, however, are completely asymptomatic and cause no demonstrable pathology.
In the past decade more than 3,500 individuals have been injected with Sanaria-manufactured P. falciparum sporozoites (PfSPZ) in more than 40 clinical trials. These trials have shown that intravenous inoculation of 2,700,000 PfSPZ causes no discernable side effects attributable to the liver stage infection. Liver function tests remain normal, and the recipient feels completely healthy. Even infants can tolerate intravenous injections of at least 1,800,000 PfSPZ without side effects. As the PfSPZ go exclusively to the liver after intravenous injection, and cause no harm to the recipient, they constitute an extraordinary method to target hepatocytes (liver cells) with antigens and/or immunomodulatory molecules.
Recently, it has been possible to genetically alter the genome of P. falciparum using CRISPR-CAS9 and related technologies, so that it expresses whatever genes are inserted. SIGHTM has recognized that this represents an extraordinary opportunity to affect the immunological milieu of the liver thereby improving the prognosis for the many diseases that chronically affect the liver, ranging from chronic hepatitis B to primary liver cancer to metastatic cancer originating in other organs. Examples of molecules that can be expressed by PfSPZ include:
Antigens from other stages of the malaria life cycle, such as protective antigens from the blood stages and sexual stages (the sexual stages are the stages transmitted back to the mosquito vector).
Antigens from one of the four other Plasmodium species that cause human disease, for example, the second most common malaria parasite, P. vivax.
Antigens from other infectious agents (e.g., hepatitis B core antigen), which could be used to strengthen the immune response in the liver and end chronic infection.
Immunomodulatory molecules that could stimulate the immune system (interferon gamma, interleukin 2) if that is what is needed to interrupt a diseases process. These molecules would perform an adjuvant function by generating a strong immune response against an infectious agent or against cancer cells.
Immunomodulatory molecules that could suppress the immune response when the disease is caused by an overactive immune response. An example would be preventing the rejection of liver transplants by the host immune system.
SIGHTM proposes to tackle chronic hepatitis B as a first target. Chronic hepatitis B (CHB) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Following acute hepatitis B virus infection, 5% to 10% of adults and up to 90% of children fail to produce an immune response adequate to clear the infection; these individuals become chronic carriers of the virus, presently accounting for 250-300 million people. Individuals who develop CHB are at substantial risk of cirrhosis, hepatic decompensation, and HCC, which will afflict 15% to 40% of patients with CHB in the absence of effective treatment and accounts for 654,000 deaths annually, a top 20 cause of mortality globally. Vaccination using the available hepatitis B vaccine (Recombivax HB), consisting of recombinant HBsAg produced in yeast and formulated in alum, is not effective in patients with CHB.
The host immune response to hepatitis B virus infection plays a pivotal role in whether acute infection is resolved or becomes chronic. Individuals who can clear hepatitis B virus spontaneously following an acute infection display a vigorous, polyclonal, virus-specific CD8+ and CD4+ T cell response. In contrast, CHB is associated with a limited and dysfunctional CD8+ T cell response, as well as impaired natural killer cell antiviral function. SIGHTM proposes that PfSPZ expressing the right combination of hepatitis B antigens and immunostimulatory molecules will tip the scales of the immune response and allow patients suffering from CHB to cure their infection.