Advances in immunological control of neurocysticercosis

Cysticercosis due to Taenia solium is one of the most prominent diseases of zoonotic importance causing significant morbidity and mortality in humans. Cysticercosis, or tapeworm infection, is the most common central nervous system (CNS) parasitic infection worldwide. Taenia solium and Neurocysticercosis (NCC) remains a major public health problem in developing countries. NCC is a parasitic infection caused by the larvae of Taenia solium which affects humans mainly by accidental ingestion of eggs containing infective oncosferes which affact the brain and CNS. NCC is the most common cause for adult occurrence of seizures, and onset epilepsy in less developed countries. Cysticercosis was first described in pigs by Aristophanes and Aristotle in 3^rd century BC. Latter it was noticed in human by Parunoli in 1550. Cysticercosis has also been described in ancient Indian medical book, the Charak Sanhita. However, NCC was first reported in India from Madras, who died due to seizure and was found to be infected with cyst on autopsy.

When the oncospheres are ingested by human or pig, the embryos are released in the intestinal wall, by the action of bile and digestive enzymes, the scolex of a cysticercusevaginates and attaches to the intestinal wall, and enter in the mesenteric venule or lymphatics and carried to the circulation in different part of body. They are infiltrated principally in the muscles where they develop in to larval stage cysticercus cellulosae.  Cysticerci reach their final size of approximately one cm in 2-3 months and may live as long as five years. Outside of the central nervous system and eyes, cysticercosis does not result in major physiological effects. Common places of lodging of the parasite in CNS include meninges, parenchyma of brain and spinal cord, subarachnoid space, and intraventricular spaces and rarely in eyes.

Physiological studies have shown that presence parasites in the subarachnoid space, near the central nervous system arteries that form the circle of Willis cause severe inflammatory reaction. Further the parasite infects the middle-sized cerebral arteries that lead to occlusion of main trunk of an intracranial artery. Subarachnoid NCC is a more complex form of the disease; that causes occlusion of both perforating arteries and large arteries (middle cerebral artery and carotid artery). Cysticercosis of the subarachnoid space of the convexity is probably the most common form of subarachnoid NCC in endemic countries and may appear as a solitary cyst or as multiple cysts. The majority of these patients develop neither hydrocephalus nor cerebral infarction. However, seizures are common. This subtype of NCC may provoke an inflammatory reaction around middle- and large-sized arteries, leading to their occlusion. Bilateral occlusion of both middle cerebral arteries has also been reported.

Animals/ patients affected by NCC of the sylvian cisterns raised intracranial pressure syndrome. The occlusion of the main trunk or branches of the middle cerebral artery occurs as a consequence of severe arteritis due to large racemose cysts. Cysticercosis of the basal cisterns around the brainstem is also common. Focal deficits can occur as a consequence of chronic compressive arachnoiditis. Some patients may have a hemiparesis as the initial presenting complaint due to arteritis of the circumferential arteries of the brainstem. Hemorrhagic stroke associated with NCC includes intracystic hemorrhage, cerebral hemorrhage secondary to an inflammatory arteritis of the small perforating branches, and subarachnoid hemorrhage secondary to the rupture of a mycotic aneurysm.Rupture of a concomitant aneurysm can be favored by the presence of a severe inflammatory process in the thickened leptomeninges around the dilated vessel. Further, studies also suggested that NCC might influence the poor outcome of certain human cancers particularly glioma and haematological malignancies.

Currently available measures for control of the disease are inadequate and there is a need for new and improved interventions. Efforts are being made for development of vaccines which can prevent T. Solium being transmitted by pigs, the parasite’s natural intermediate host; a highly effective vaccine, able to prevent infections in neonates as well as adult pigs, an inexpensive vaccine which can be delivered via an edible biscuit, without the need for equipment or trained personnel. Through the combined use of anthelmintics, vaccination of pigs and public awareness about the disease, the parasite could be eradicated.

Initial works on the development of vaccines demonstrated that protection could only be achieved by exposing hosts to living parasites. However, a breakthrough was made by Rickard and Bell (1971) who demonstrated significant levels of protection against Taenia ovis infection in lambs in which T. ovis oncospheres had been grown intraperitoneally in diffusion chambers. Subsequently, protection was achieved in vaccine trials using cell-free antigen preparations collected by culture of oncospheres in vitro and with antigens prepared directly from oncospheres. The high success rate of vaccine trials using oncosphere antigens presents a ray of hope for development of practical vaccines; however, the problem encountered was the mass production of antigen which could be used for vaccine production on a large scale. The development of recombinant DNA technology paved a way for large scale production of antigen.

The recombinant antigen vaccine developed by Johnson et al in 1989 against cysticercosis caused by T. Ovis in sheep was the first effective, defined antigen vaccine against a parasitic infection and has been recognised as a milestone in the history of parasitology. Successful development of a vaccine against T. ovis encouraged efforts to develop similar vaccines against other Taenia species causing cysticercosis. The first of these was a vaccine against Taenia saginata infection in cattle. The T. ovis vaccine was developed as a result of extensive investigations which tried to identify native oncosphere antigens capable of inducing host-protective immunity. These studies involved many vaccination and challenge trials in sheep which could not be envisaged for T. saginata infection in cattle because of the cost involved in undertaking cattle trials and because of the substantial difficulties in obtaining sufficient oncospheres for these purposes. The approach which was taken to develop a vaccine against T. saginata was to utilise the information which had been obtained for T. ovis with regard to the identity of the host-protective antigens.

As with all other taeniid cestodes which were studied for vaccine development, oncosphere antigens of T. Solium have been found to be a rich source of host protective antigens. The overwhelming success which had been achieved with identifying host-protective recombinant antigens for T. saginata encouraged the adoption of a similar approach for development of a vaccine against T. solium cysticercosis in pigs.

            Other approaches have also been followed to develop a vaccine against T. solium. Antigens derived from the rodent parasite Taenia crassiceps are being used as a potential source of host-protective antigens for T. solium. This concept is based on the well-established immunological cross-reactivity between host-protective antigens derived from different taeniid cestode species.

The prospects are quite promising for the successful development of an effective, practical vaccine to assist with control of transmission of T. solium. It may be hoped that a vaccine with desirable features expressed earlier will be at our disposal very soon. The vision for an edible, nonliving vaccine is out of reach at the present time. Nevertheless, it is likely that the substantial global interest in the field of oral vaccines will lead to effective delivery strategies which could be applied to a T. solium vaccine.