SMALLPOX AND RELATED POXVIRUS INFECTIONS IN THE SIMIAN HOST NICHOLAS HAHON U. S. Army Chemical Corps, Fort Detrick, Frederick, Maryland I. Introduction ....................................................... 459 II. Variola-Vaccinia Group of Poxviruses ...................................................... 460 III. Nature of Poxvirus Infections in Simian Host .............................................. 461 A. Clinical Disease in Relation to Route of Virus Inoculation ................... 461 1. Variola.............................................................................. 461 2. Vaccinia ...................................................... 463 3. Monkeypox.......................................................................... 464 4. Factors affecting resistance.......................................................... 464 B. Species Susceptibility................... .... .... 464 C. Pathogenicity and Virulence of Poxvirus Strains ........................ 465 D. Pathology in Relation to Route of Virus Inoculation .................................... 467 1. Variola.............................................................................. 467 2. Alastrim............................................................................ 467 3. Vaccinia............................................................................ 468 4. Monkeypox......................................................................... 468 E. Cross-Immunity Relationships ................................. 468 F. Assessment and Duration of Immunity ................................................. 469 G. Pathogenesis ..........:. ............. ................. 470 IV. Appraisal of Simian Smallpox in Relation to Public Health . 471 V. Comment ...................................................... 473 VI. Literature Cited ..................................................... 474 I. 1NTRODucrioN incubation and disease, the duration of protec- A sense of complacency resulting from the ap- tion following vaccination, the pathogenesis of parent control of smallpox may be one of the the vaccination process, and the evaluation of factors responsible for the lack of interest in basic chemotherapeutic agents are some aspects of the studies with its etiological agent. The constant disease that may be resolved through the use of vigilance practiced by public health authorities an experimental host. to prevent the importation of smallpox and the The study of experimental smallpox, however, prompt vaccination of suspected contacts have has been limited because of the narrow range of been significant deterrents to its spread in the animals that are susceptible to the virus. Mon- 'Testern Hemisphere. Nevertheless, smallpox keys appear to be the only experimental animal remains a continual threat to man, as evidenced in which the pattern of disease is similar to that by its endemicity in certain localities of the of human infections. Although some fundamental Middle and Far East, by occasional outbreaks of studies were performed with the virus of small- epidemic proportion in those areas, and by pox in this host more than 50 years ago (11), sporadic cases of the disease throughout the world. relatively little work has been done in subsequent The disease persists, although vaccination against years. Most of the investigations have been con- smallpox has been practiced for over 160 years. cerned with cross-immunity relationships and Although smallpox infection of man has been with attempts to convert smallpox virus to described in detail from the standpoint of vaccinia virus. symptomatology, diagnosis, pathology, im- It is the purpose of this article, therefore, to munity, and mortality rates of epidemics,-none- review the pertinent literature on smallpox and theless there are areas in which our understanding related poxvirus infections of the simian host, to of this disease requires elucidation. For example, define some of the obstacles inherent to the study the site or sites of initial multiplication of the of poxviruses in monkeys, and to stimulate virus, the pathways of virus dissemination during further basic investigation of these viruses. 459 460 NICHOLAS HAHON [VOL. 25 II. VARIOLA-VACCINIA GROUP OF POXVIRUSES immunological relationship of certain viruses "Poxvirus" has been adopted as a convenient serves as the basis for the formation of a sub- term to denote a number of viruses which have group of the poxviruses, the variola-vaccinia many features in common, although they com- group. Members of this group are variola (small- prise several immunologically unrelated sub- pox), alastrim, rabbitpox, vaccinia, monkeypox, groups (3). The criteria for inclusion in the group cowpox, and ectromelia (mousepox). Because of are: (i) large virus particles of rounded quad- the scarcity of published information regarding rangular form, with the longest diameter in the the infectivity of rabbitpox, cowpox, and mouse- range of 200 to 250 mnu; and (ii) predilection for pox viruses for the simian host, only casual infection of skin epithelium, with formation of reference will be made to these viruses. cytoplasmic inclusion bodies (24). The close In addition to the property of related anti- TABLE 1. Susceptibility of monkeys to related poxviruses Virus and host species Route of inoculationa Signs of infections Reference Variola: Macaca cynonmolgus S, Sc, C, MM, IC, R LL, F, GE 11, 20 Macaca irus R. IT, IN F, GE 38, -d Saimiri sciureus R F, GE Macaca sinicus ITT OR, F, GE 59 Cercopithecus callithrix ITT, S OR, F, GE 60, 69 Macaca rhesus SC, IN, ID-IP, R, 0 LL, F, GE -, 53, 69 Macaca nemestrinus S, IT, 0, IV LL, F, GE 11, 40, 58 Cercopithicus pathas S LL 60 "Macacus" SC, S LL, F, GE 4, 30, 46, 61 "Rhoesus" SC, S LL, F, GE 17, 36, 46, 61 "Cercopithecus" 0, ID LL, GE 70 "Large African monkey" SC LL 30 "Java" SC LL 49 Simia satyrus S, R? LL, GE 10, 11 Alastrim: Macaca rhesus IV, SC LL, F 16, 19, 44 Macaca cynomolgus S LL 44 Macaca sinicus SC Nonec 63 Cercopithecus sebacus S, IV LL, F, GE 40, 65 "Monkey" ICA GE 21 "Rhoes us" S LL 36 Vaccinia: MIacaca cynomolgus IC, SC, S, C, MM LL, E 1 ,11, 20 Cercopithecus sebacus S LL 40 Cercopithecus mona SC LL 56 Cercopithecus albigularis ID LL, E 15 Cebus apella SC LL 56 "Rhesus" SC LL 37, 56 "Java" 0 LL 7 "Cynocephale" S LL, F 69 "Bonnet" SC LL, F 7 Macaca irus R F, D a SC = subcutaneous, S = scarification, C = cornea, MM = mucous membranes, R = respiratory, IC = intracerebral, IT = intratracheal, ITT = intratesticular, 0 = oral, ID = intradermal, ICA = intracardial, IP = intraperitoneal. I LL = local lesion, F = fever, GE = generalized exanthem, OR = orchitis, E = encephalitis, and D = death. c There is a question as to whether the virus was alastrim. d -= N. Hahon, unpublished data 19611 POXVIRUS INFECTIONS IN SIMIAN HOST 461 genicity shared by members of the variola- TABLE 2. -Comparative occurrence of exanthem in vaccinia group, the ability to form lesions or Macaca irus after. intratracheal inoculation of pocks upon inoculation of the chorioallantoic the Yamada and Kali-Muthu strains of variola membrane of embryonated eggs by each of the virus viruses serves as another point of similarity. Proportion of inoculated animals Individually, the viruses appear to differ from developing exanthem Virus quantity inocula- each other in their range of infectivity. Variola ted, infectious units"ali-MuthuYamada Kl-uh and alastrim have a limited range of patho- (egg-passaged) (human scab genicity for experimental animals but are preparation) transmissible naturally to man. Cowpox and 3 .0 X 1 0 2/3b 1/3 rabbitpox are natural diseases of cows and rab- 3.0 X 103 2/4 1/4 bits. The former is transmissible to man; the 3.0 X 102 3/3 0/3 latter has not been reported to be transmissible 3.0 X 10' 1/3 0/2 to man. Mousepox and monkeypox are natural Total no. infected.". 8/13 2/12 diseases of the species for which they are named. Per cent infected'.. 61 16 The former is not transmissible to humans and a the pathogenicity of the latter for man has not Enumeration of pocks formed on the chorio- been determined. Although vaccinia virus allantoic membrane of embryonated eggs. b Numerator = number of animals with ex- possesses the widest range of for infectivity anthem, denominator = number of. animals in- animals of all the viruses in the group, it is unique oculated. in that it does not occur naturally. a. Intradermal. The clinical disease in mon- III. NATURE OF POXVWS INFECTIONS IN SIMIAN ST keys, following dermal inoculation with variola virus, may also exemplify the infection after A. Clinical Disease in Relation to Route of other routes of injection. The overt signs of small- Virus Inulation pox infection in the monkey may consist of (i) a Monkeys may be infected by almost any route local lesion at the site of dermal inoculation, of inoculation with the poxviruses, variola, (ii) vague constitutional disturbances, (iii) a alastrim, and' vaccinia, but the reaction may slight or marked elevation of temperature, and vary from a local lesion at the site of inoculation (iv) an exanthem of varied intensity. to a generalized exanthem (Table 1). The route A reaction appears on the skin at the site of of virus injection, the strain of virus, and the inoculation in 3 days, and, on the sixth to seventh species of monkey, however, may influence the day, when the primary lesion is most active, body response of the host to infection, either in- temperature rises and may peak at 105 F or dividually or concertedly. higher (11). Other constitutional signs that may