Brazilian researcher details efforts to find future-generation smallpox vaccines

A study published online in the most recent Journal of Virology issue says that because the fear exists that some form of the variola virus – the pathogen that causes smallpox -- could be reintroduced to humans in the form of a biological weapon, it is essential that a new generation of smallpox vaccines be developed.

“A better understanding of how all the strains relate to each other and finding new clones that may be used to develop new smallpox vaccines are of great value,” Clarissa Damaso, associate professor at the Universidade Federal do Rio de Janeiro in Brazil, said.

In an effort to support the development of such smallpox vaccines, Damaso was the lead researcher on a team from Brazil, Germany and the United States that recently completed a study of the vaccinia virus (VACV) used in the development of the smallpox vaccine.

Entitled, "Genomic analysis, phenotype, and virulence of the historical Brazilian smallpox vaccine strain IOC: Implications for the origins and evolutionary relationships of vaccinia virus," the study details how the researchers used two clones of VACV-IOC, which is the smallpox vaccine strain used to eradicate smallpox in Brazil, and compared their virulence and immune response to other VACV strains.

“Vaccinia virus was used as the smallpox vaccine for decades,” Damaso told BioPrepWatch. “Several vaccinia strains were used successfully worldwide to eradicate smallpox.”

However, first-generation vaccines used to eradicate smallpox had rates of adverse effects that are not acceptable by current health care standards, according to the study. Moreover, these vaccines are genetically heterogeneous and consist of a pool of quasi-species of VACV, making the search for new-generation smallpox vaccines that combine low pathogenicity, immune protection, and genetic homogeneity extremely important.

Specifically, Damaso said, the team “studied the biological, immunological and genetic properties of the first-generation smallpox strain manufactured in Brazil – VACV-IOC. We obtained two clones of this first-generation vaccine and we showed that they are low virulent to mice, induce very good immune response and protect mice from a lethal challenge with a virulent strain of vaccinia virus.”

The immunogenicity and reduced virulence make the IOC clones good options for alternative second-generation smallpox vaccines and more importantly, the study reveals the phylogenetic relationship between VACV-IOC, feral VACV established in nature, and the ancestor-like horsepox virus, she said.

Damaso told BioPrepWatch that the best future-generation smallpox vaccines “would be made of non-replicating virus or, even better, recombinant protein subunits." She said there have been some attempts to create smallpox vaccines from inactivated viruses, but they were not successful.

“Recombinant protein subunits would be great, but we have to remember that smallpox has been eradicated and there is no animal model for this disease to test the efficacy of new vaccines,” she said. "One of the best options is to use second-generation vaccines, i.e, non-virulent but immunogenic clones, isolated from first-generation smallpox vaccines.”

The American vaccine Acam2000 is a second-generation smallpox vaccine obtained by clonal selection of the old Dryvax vaccine. In its work, the study team isolated the two low-virulent clones – B388 and B141 – of the Brazilian first-generation smallpox vaccine – VACV-IOC, Damaso explained.

“Their responses were very similar to the protection effect of Acam2000, but we haven’t done any experiments in humans, only in mice,” Damaso told BioPrepWatch. “We also sequenced the full genome of both clones of VACV-IOC and compared with the full genome sequence of several vaccinia virus strains.”

This is particularly important, she said, because the history of the smallpox vaccine virus is quite obscure and unknown.

“We show that VACV-IOC forms a new group in the phylogeny of vaccinia virus and is close, yet it forms a distinct group from the American Dryvax clones, including Acam2000,” she said. “We associated our genetic data with a historical investigation and the data suggest that the American Dryvax strain may have derived from the same source of vaccine as VACV-IOC. Our data expand the discussion on the origins and evolutionary connections of VACV lineages."