Vaccines

In 1798, Edward Jenner published results of his experiments which showed that previous infection with cowpox - variolae vaccinae - protected humans against challenge with smallpox. Although the original observation can be traced back to country folklore, Jenner was the first to test the hypothesis scientifically. He had also to contend with the difficulty that cattle could be infected with either cowpox, an orthopoxvirus which did protect, or the clinically similar pseudocowpox, a parapoxvirus which did not confer protection. In 1881, Pasteur defined the term 'vaccination' to include any form of prophylactic inoculation.

At what stage cowpox virus was replaced by vaccinia is not clear. Even the origin of vaccinia is not known: suggestions include horse pox, which is now extinct, or a recombinant derived from cowpox and smallpox. Regardless of origin, cowpox vaccinia was

Table 2 Poxvirus encoded factors which interact with the host immune system

Host factor/mechanism

Virus-encoded homolog

Function

Complement control proteins

Cytokine receptors

Serine protease inhibitors (serpins)

Interferon

MHC class I antigen presentation

Growth factors

Steroid hormones

Vaccinia complement control protein

IL-1 receptor W, CPV

TNF receptor SFV, M, VV

IL-8 receptor SPV

W (E3L) dsRNA binding protein

W (K3L) PKR binding protein

W Late protein M Late protein

Epidermal growth factor Transforming growth factor « W, SFV, M

Vascular endothelial growth factor OV 3P-HSD W

Secreted from infected cell binds C4b and C3b and blocks complement activation Sequence homology only, membrane bound Binds IL-1 (3 and abrogates function Binds IFN7 and abrogates function Binds TNF« and abrogates function Sequence homology only Prevents apoptosis in RPV Inhibits pro-IL-1f$ converting enzyme/alters arachidonic acid metabolism Inhibits cell-cell fusion; reduces inflammation

Blocks PKR activation by competitively binding dsRNA

Functions as a substrate for PKR preventing phosphorylation of elF2a Reduction in surface MHC class I expression and a block in the presentation of specific peptides to cytotoxic T lymphocytes Promote cell growth and virus replication

Synthesizes steroid hormones and reduces inflammation

CPV, cowpox virus; M, myxoma virus; OV, orf virus; RPV, rabbit pox virus; SFV. shope fibroma virus; SPV, swinepox virus; VV. vaccinia virus: PKR, double-stranded RNA-dependent protein kinase; 3|3-HSD, 3p-hydroxysteroid dehydrogenase; TNF. tumor necrosis factor. Gene designations are given in parentheses.

extremely valuable in helping to reduce the mortality rate due to smallpox and ultimately to the declaration, on 9 December 1979, that the disease had been eradicated from the world.

Complications associated with vaccination against smallpox were initially ignored as being insignificant compared with the consequences of infection. But as the industrial countries eradicated smallpox, it was seen that more patients were suffering the effects of vaccination than were being infected with smallpox. Complications included eczema vaccinatum in patients suffering from eczema, progressive vaccinia in patients with cell-mediated immune deficiency or agammaglobulinemia, generalized vaccinia, accidental infection, postvaccinal tonsillitis, postvaccinal encephalopathy in infants under 2 years old, and postvaccinal encephalitis in patients over 2 years old. In a very large survey carried out by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in 1968, 75 people per million given primary vaccination had associated complications, and, of these, 1 per million died, either of postvaccinal encephalitis or progressive vaccinia. Following secondary vaccination only 5 people per million had associated complications.

Vaccinia has also been used successfully in veterinary medicine to control camelpox, although it is less efficient in controlling ectromelia. However, less successful has been its apparent persistence in buffaloes as buffalo pox, and in rabbits as rabbit pox. How vaccinia was introduced to these species is not certain, but there are numerous examples of the transmission of the virus from recently vaccinated dairy-farmers to the udders of their cows.

Sheep, goats and cattle can be effectively vaccinated against capripoxvirus infection, and single vaccines are available to protect all three specics. Similarly, pigeon pox virus is effective in protecting chickens and turkeys against fowlpox and turkey pox. Separate vaccines are required against quail pox and against psittacine pox. Shope fibroma virus provides good protection in rabbits against myxomatosis, although it is less effective than homologous vaccine.

Vaccination against parapoxvirus infection is considerably less effective than that against ortho-, capri-, avi- or leporipoxvirus infection. Even against challenge with the homologous virus strain, contagious pustular dermatitis vaccine gives only limited protection.

Dead vaccines against smallpox and capripox have been developed, but at best these have provided only temporary protection, compared with the prolonged protection provided by live vaccines. Part of the initial failure was due to the use of unenveloped virus derived from disrupted cells. Poxvirus in tissue culture is highly cell-associated, and yields of extracellular, enveloped virus are small. However, even when this problem had been recognized, further attempts to develop effective dead vaccines have been unsuccessful.

Poxvirus recombinants are valuable research tools; by facilitating the expression of individual gene products or particular epitopes, specific immune responses can be studied in isolation from the whole pathogen. This approach has helped to identify and decipher individual components of the immune system, including the relative functions of particular T cell subsets. More recently, there has been a revival in interest in vaccinia as a vector for the genes of pathogens such as hepatitis B, rabies, rinderpest, Plasmodium, respiratory syncytial virus, vesicular stomatitis and human immunodeficiency virus (HIV). The advantages of having a replicating vector expressing the antigens of these agents are self-evident. Vaccinia virus is genetically stable, easy to produce and apply, and nononcogenic. The disadvantages of its use as a vector are its possible virulence in nontargeted hosts including humans, the possibility that it could recombine with other poxviruses in the field, and the effect it could have on immunodeficient individuals. Veterinary vaccines using capripoxvirus or avipoxvirus vectors may prove to be more acceptable than those incorporating vaccinia virus.

See also: Vaccines; Viruses, immunity to. Further reading

Alcami A and Smith GI. (1995) Cytokine receptors encoded by poxviruses: a lesson in cytokine biology. Immunology Today 16: 474-478. Fenner F, Henderson DA, Arita 1, Jczek Z and I.adnyi ID

(1988) Smallpox and its Eradication. Geneva: WHO. Kitching RP (1987) Vaccination against pox disease. Veterinary Annual 27: 10.9-114. McFadden G (ed) (1995) Viroceptors, Virokines and Related Immune Modulators Encoded by DNA Viruses. Heidelberg: Springer. Moyer RW and Turner PC (eds) (1990) Poxviruses. Current Topics in Microbiology and Immunology 163. Springer.

Murphy FA, Fauquet CM, Bishop DHL et al (eds) (1995) Virus Taxonomy, Classification and Nomenclature of Viruses, Sixth Report. New York: Springer.

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