Vaccinia Virus Natural Infections in Brazil: The Good, the Bad, and the Ugly

Abstract

The orthopoxviruses (OPV) comprise several emerging viruses with great importance to human and veterinary medicine, including vaccinia virus (VACV), which causes outbreaks of bovine vaccinia (BV) in South America. Historically, VACV is the most comprehensively studied virus, however, its origin and natural hosts remain unknown. VACV was the primary component of the smallpox vaccine, largely used during the smallpox eradication campaign. After smallpox was declared eradicated, the vaccination that conferred immunity to OPV was discontinued, favoring a new contingent of susceptible individuals to OPV. VACV infections occur naturally after direct contact with infected dairy cattle, in recently vaccinated individuals, or through alternative routes of exposure. In Brazil, VACV outbreaks are frequently reported in rural areas, affecting mainly farm animals and humans. Recent studies have shown the role of wildlife in the VACV transmission chain, exploring the role of wild rodents as reservoirs that facilitate VACV spread throughout rural areas. Furthermore, VACV circulation in urban environments and the significance of this with respect to public health, have also been explored. In this review, we discuss the history, epidemiological, ecological and clinical aspects of natural VACV infections in Brazil, also highlighting alternative routes of VACV transmission, the factors involved in susceptibility to infection, and the natural history of the disease in humans and animals, and the potential for dissemination to urban environments.

Keywords: ecology; host range; natural infections; orthopoxvirus; public health; smallpox vaccine; vaccinia virus; zoonosis.

Figure 1

Detection and distribution of vaccinia virus (VACV) in South America. (A) A map of South America is shown on the left and the green pins indicate countries where VACV has been detected in recent years. The red pin indicates the absence of VACV detection in French Guiana; (B) A map of Brazil highlighting the distribution of VACV in different regions and the detection of VACV in a broad range of hosts. The antibodies (blue) indicate serological evidence of VACV circulation in humans in rural areas of Acre state. Dashed lines in different colors represent VACV circulation in different Brazilians states, i.e. red dashed lines represent VACV circulation in Minas Gerais State, black dashed lines represent circulation in São Paulo State, and green dashed lines represent circulation in Pará State.

Figure 2

Clinical presentation of bovine vaccinia infection in dairy cattle and humans. (A) Nodular and ulcerative lesions on the udder and teats of dairy cows; (B) The classical transmission of VACV involves direct contact between dairy workers and infected cows; (C) Nodular and ulcerative lesions on hands and forearms of rural workers; (D) Additional systemic symptoms present during VACV infection in humans (Source: [43,53,54,55]).

Figure 3

Phylogenetic analysis based on the A56R gene of VACV vaccine and wild isolates, with cowpox virus (CPXV) sequences included as an outgroup. These sequences are available in the NCBI nucleotide database under the GenBank Accession Numbers provided in brackets on the tree. The sequences were aligned by using ClustalW algorithm and the evolutionary history was inferred by using the Maximum likelihood (ML) method, using Mega 7.0 (GE Healthcare, Buckinghamshire, UK) software and the Jukes-cantor model was selected for ML inference by the program JmodelTest 2.1.6 (Free Software Foundation, Inc., Boston, MA) The evolutionary distances were computed using the Maximum Composite Likelihood method with 1000 Bootstrap replicates. The analysis involved 65 nucleotide sequences with a total of 734 positions in the final dataset. Evolutionary analyses were conducted in Mega 7.0 software.

Figure 4

Distribution of artisanal cheese samples in four different dairy basin in Minas Gerais state. (A) Map of Brazil highlighting where Minas Gerais state and Belo Horizonte city are located; (B) All samples were collected in Belo Horizonte city, in the central area of Minas Gerais; (C) An example of artisanal cheese produced in Minas Gerais state; (D) Nucleotide sequence of the VACV detected in commercial artisanal cheese samples (blue) C11R (viral growth factor) gene compared with homologous sequences of several other orthopoxviruses. The amplified fragments were sequenced in both orientations by the dideoxy method in an ABI3130 platform (Applied Biosystems, Foster City, CA, USA), and sequence quality was analyzed by using Sequence Scanner Software 1.0 (Applied Biosystems, Foster City, CA, USA). Sequences were aligned (ClustalW (http://www.genome.jp/tools/clustalw). Information regarding chesse samples processing has been included as Supplementary Material.

Figure 5

Hypothetical model highlighting the dynamic of vaccinia virus circulation in different hosts from wild, rural and urban environments. VACV outbreaks have been largely described in rural areas, affecting mainly dairy cattle and milkers. Equids have also been affected, although there are no human cases associated with direct contact with horses. Peridomestic rodents have been postulated as the link between bovine vaccinia (BV) outbreaks in dairy farms and VACV circulation in wildlife. Wild rodents could act as VACV reservoirs and transmit the virus to other small mammals, as well as peridomestic rodents, thus maintaining the wild-rural cycle. In urban areas, the dynamic also involves wild rodents that could be in contact with other mammals such as capybaras and coatis. These wild species can interact with domestic animals such as dogs and cats that live in regions bordering green areas (natural parks and forest reserves), which could favor VACV spread and transmission to other domestic animals and humans. Alternatively, VACV could be disseminated to urban areas through contaminated dairy products. Solid lines represent hypotheses already described. Dashed lines indicate new hypotheses pointed out by our group.