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Plotkin: Progress in vaccination

Vaccines have prevented more disease than any other modality, except clean water. This point was made in the first edition of Vaccines, the textbook that is now in its sixth edition, and which has grown from 1400 g to 4500 g. As examples, the rubella vaccine is in the process of eradicating the disease, the rabies vaccine could do so if it were more generally available, the rotavirus vaccine is just now being applied and the cytomegalovirus vaccine is in development. Interest in rubella began in the 1940s with the observation by an Australian ophthalmologist that infection of pregnant women led to congenital abnormalities in their infants, including cataracts, deafness, congenital cardiac malformations and intellectual disability. We set about to attenuate rubella virus in WI-38, a human diploid cell. After a limited number of passages at 37°C, the incubation temperature was lowered to 30°C. Clinical trials conducted at various passage levels confirmed increasing attenuation, and by the 25th passage it appeared that a good level of attenuation had been obtained without damaging immunogenicity. Seroconversion occurred in 95% or more of vaccinees and, when exposed to rubella, protection was seen in about 95% of them. The vaccine strain, called RA 27/3, is usually incorporated with measles and mumps strains to be given as the triple vaccine, MMR. The application of rubella vaccination has resulted in the elimination of endogenous infection from North America, Latin America and indeed from the entire Western Hemisphere. In Europe, Scandinavia is now free of the rubella virus. Many countries in Asia have begun to vaccinate against rubella, and even in Africa some countries have instituted rubella vaccination through the use of MR or MMR. As there is no animal reservoir of the rubella virus, eradication of the virus can be accomplished, and we can hope that congenital rubella syndrome will become a disease of the past.

Rabies has been called the incurable wound and, in fact, few people survive infection. The earliest rabies vaccines were made by injection of the virus into the central nervous system of laboratory animals and then collecting the infected brain material for human inoculation. This brain tissue could cause severe autoimmune reactions and, as it contained such low titres of the virus, repeated inoculation was required (as many as 21 times). The advent of cell culture allowed for growth of the virus to high titres. The best cell appeared to be the same human diploid cells chosen for rubella virus attenuation. Immunization with rabies virus grown in cell culture and then inactivated was safe and could induce high titres of protective antibody against the virus and protect against exposure. The virus was adapted to other cell types, notably African green monkey kidney Vero cells and chick embryo cells. An additional value of the cell culture products is that they can be delivered via both the intradermal and intramuscular route.

Gastroenteritis is a major killer of infants. An estimated 450 000 infants die each year as a result of rotavirus infection. The rotaviruses contain double-stranded RNA, with 11 separate segments, each coding for a protein. Rotaviruses infect and cause diarrhoea in many species of mammals, but each species is infected by a different group, so that there are mouse rotaviruses, bovine rotaviruses, monkey rotaviruses, etc. We created new reassortants which contained 10 RNA segments from a bovine virus and one segment from a human virus coding for the VP7 gene of G1, G2, G3 or G4 serotypes. In addition, a fifth reassortant was created, containing an RNA segment coding for a protein called VP4, also capable of inducing neutralizing antibodies. The particular VP4, called P1A, is the most common in human rotaviruses. The idea was to induce a neutralizing response against all of the common human strains. Heterotypic immunity is also induced, and thus there is also protection against serotypes not in the vaccine. Another group, located at the Cincinnati Children’s Hospital, successfully attenuated a single strain of human rotavirus by serial passage in cell culture. The pentavalent vaccine was introduced into routine vaccination in the USA in 2006, with three oral doses recommended at 2, 4 and 6 months of age. The effect on rotavirus disease was immediate, with a sharp reduction in laboratory diagnoses of infection and in admissions to hospital caused by rotavirus gastroenteritis. There was also evidence of a herd effect – fewer cases in unvaccinated infants. The monovalent vaccine also showed high efficacy. However, when the two vaccines were tested in developing countries the efficacy was much lower. Much investigation is being conducted to determine the reason for the differences in efficacy between developed and developing countries. Possible explanations for the lower efficacy in developing countries include neutralization by antibodies in breast milk, neutralization by higher maternal antibodies, interference by other viruses and changes in the small intestine caused by those prior infections. Nevertheless, from a public health point of view, because of the high incidence of serious and fatal gastroenteritis in tropical countries, even a reduction of 50% constitutes a major beneficial effect of rotavirus vaccination, and various strategies are being explored to improve efficacy.

In the 1970s, after it became apparent that rubella vaccination would eventually do away with congenital rubella, the importance of congenital cytomegalovirus (cCMV) infection became evident. Indeed, it has since been confirmed that cCMV occurs in 0.5% to 2% of all pregnancies, and thus it is a major cause of birth defects, primarily deafness but also including severe central nervous system malformations. In addition, the era of solid organ and haematogenous stem cell transplantation revealed the importance of CMV infection and disease. Aside from fever, serious pneumonia and gastrointestinal disease, CMV increases graft rejection. We isolated and attenuated a strain called Towne from a patient with cCMV. The Towne strain was passaged in human diploid cells until it developed a deletion that restricted replication and latency in vivo. Vaccination of previously seronegative adults with a single dose reduced serious CMV disease and transplant infection by approximately 80%. Meanwhile, other avenues were pursued to develop a vaccine. The neutralizing antibody response to CMV is induced by two antigens on the surface of the virus: glycoprotein B (gB) and a pentameric complex called gH/gL/UL128/UL130/UL131. Antibodies to the complex prevent entry of CMV into epithelial and endothelial cells.

DNA plasmids have long been known to induce immune responses against the proteins coded by the DNA. Protection of haematogenous stem cell recipients against CMV viraemia and the need for antiviral treatment were demonstrated in a placebo-controlled clinical trial. The proteins generated were gB and phosphoprotein 65 (pp65), the latter being a tegument protein of the virus that is the principal inducer of cytotoxic T cells against CMV. Therefore, it appears that we already have the tools to prevent CMV disease in both solid organ and haematopoietic stem cell transplant recipients. To prevent cCMV there are several possible targets. The most obvious is the immunization of seronegative girls (11–18 years old) before they enter the child-bearing years. Vaccines could be given to older women contemplating pregnancy. From a public health viewpoint, an interesting approach would be vaccination of infants before they come into contact with other children, since they are the chief source of infection of their mothers. Such vaccination could reduce circulation of CMV.





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