Smallpox Eradication Campaign Research Articles

Comparison of the Efficacy of Different Schemes for Using Recombinant Vector Vaccines against Ebola Fever, Based on Vaccinia Virus, MVA Strain

The aim of this review was to investigate the use of the vaccines based on vaccinia virus, MVA stain, and adenovirus vectors for the prevention of Ebola virus disease. The recombinant MVA strains expressing antigen determinants of Filoviridae family representatives were assessed as possible candidates for vaccine preparations. Application of this virus as a vaccine vector is conditioned by the absence of herd immunity to smallpox and its safety for healthy adult volunteers, children, adolescents, individuals suffering from tuberculosis, persons aged 56–80 years, people with diagnosed atopic dermatitis, AIDS. Furthermore, immunization with the vaccine on the basis of vaccinia virus, MVA strain, does not cause complications associated with cardiovascular diseases. Preclinical trials on immunogenicity and protective efficiency were carried out on immune-competent and immune-compromised mice; guinea pigs adapted to Ebola virus; rhesus macaques and cynomolgus monkeys. Presented are the results of experiments on the creation of vaccines expressing either only viral glycoprotein or viral glycoprotein and structural protein Vp40. Given that Ebola fever and other filovirus infection outbreaks are hard to predict, multivalent vaccines that would be able to provide protection against all filovirus species were designed. Clinical trials on simultaneous use of the vaccines based on recombinant adenovirus vectors and MVA strain showed more pronounced safety of vaccines on the basis of recombinant MVA strain. Studies of humoral and T-cell immune responses have revealed that this vector is more suitable for booster vaccination in case of heterologous prime/booster immunization scheme. Vaccination regimens for forming strong durable immune responses have been analyzed. Epidemiological modeling provided evidence that preventive immunization leading to long-term immunity in healthy population in areas of high epidemic risk will be of greater benefit in terms of controlling future outbreaks compared to ring immunization that was effective during smallpox eradication campaign. Increased immunity level, induced by prime/booster vaccination, persisting for a long period of time, will have an advantage over accelerated ring immunization; when the duration of protection is more significant than the speed it is formed at.

Emergence and History

Emergence and History

Bureaucratic Reversals and Local Diversity

Normal bureaucracy tends to centralise, standardise and simplify, and to serve better those people and places that are less poor and more accessible. Field bureaucracies have done well (a) where simple standardised programmes have found uniform conditions – like the human body with smallpox and yaws eradication campaigns, or irrigated plains with green revolution packages, and (b) where they have created and sustained uniform conditions, as with technically exacting time‐bounded programmes for single commodities such as tea and milk. For the diverse, complex, and risk‐prone farming systems found outside green revolution areas, normal agricultural research and extension for single commodities has a more limited part to play. Reversals are needed and occurring – to perceive, permit, and promote diversity, searching for what farmers need and providing not a package of practices but a basket of choices. This complementary paradigm of reversals in agricultural research – to decentralise, and to serve diversity and complexity – raises the question of its wider relevance and application in other domains and bureaucracies, to fit and meet the varied conditions and needs of those who are poorer, less accessible, and less powerful.

Efficacy of smallpox vaccines against Mpox infections in humans.

The Mpox virus (MPXV) is endemic in certain countries in Central and West Africa, where several mammalian species, especially rodents, are natural reservoirs. However, the MPXV can infect nonhuman primates and cause zoonotic infections in humans after close contact with an infected animal. Human-to-human transmission of MPXV can also occur through direct close contact with an infected individual or infected materials. In May 2022 an initial cluster of human Mpox cases was identified in the UK, with the first case confirmed in a patient who had recently travelled to Nigeria. The infection subsequently spread via human-to-human transmission within the UK and Mpox cases began to appear in many other countries around the world where the MPXV is not endemic. No specific treatments for MPXV infection in humans are available. However, data from studies undertaken in Zaire in the 1980s revealed that those with a history of smallpox vaccination during the global smallpox eradication campaign also had good cross-protection against MPXV infection. However, the vaccines used during the global eradication campaign are no longer available. During the 2022 global Mpox outbreak over a million doses of the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) smallpox vaccine were offered either as pre or postexposure prophylaxis to those at high risk of MPXV infection. Here, we review what has been learned about the efficacy of smallpox vaccines in reducing the incidence of MPXV infections in high-risk close contacts.

Monkeypox virus: The changing facets of a zoonotic pathogen.

In the last five years, the prevalence of monkeypox has been increasing both in the regions considered endemic for the disease (West and Central Africa) and worldwide. Indeed, in July 2022, the World Health Organization declared the ongoing global outbreak of monkeypox a public health emergency of international concern. The disease is caused by monkeypox virus (MPXV), a member of the Orthopoxvirus genus, which also includes variola virus (the causative agent of smallpox) and vaccinia virus (used in the smallpox eradication campaign). Here, we review aspects of MPXV genetic diversity and epidemiology, with an emphasis on its genome structure, host range, and relationship with other orthopoxviruses. We also summarize the most recent findings deriving from the sequencing of outbreak MPXV genomes, and we discuss the apparent changing of MPXV evolutionary trajectory, which is characterized by the accumulation of point mutations rather than by gene gains/losses. Whereas the availability of a vaccine, the relatively mild presentation of the disease, and its relatively low transmissibility speak in favor of an efficient control of the global outbreak, the wide host range of MPXV raises concerns about the possible establishment of novel reservoirs. We also call for the deployment of field surveys and genomic surveillance programs to identify and control the MPXV reservoirs in West and Central Africa.

Monkeypox: Considerations as a New Pandemic Looms

Monkeypox: Considerations as a New Pandemic Looms

Monkeypox: Current trends and therapeutic challenges

Monkeypox is a viral zoonotic disease that mostly affects tropical rainforest regions of Central and West Africa, with infrequent exportations to other parts of the world. The cause of monkeypox is the monkeypox virus, a species of the Orthopoxvirus genus in the family Poxviridae. Monkeypox often has symptoms that last between 2 and 4 weeks and is a self-limiting condition. Severe cases could exist. Monkeypox can be spread to humans by close contact with infected animals or people, as well as through coming into contact with contaminated materials. By coming into intimate contact with lesions, bodily fluids, respiratory droplets, and contaminated things like bedding, the monkeypox virus can be transferred from one person to another. The smallpox immunizations used in the smallpox eradication campaign also provided immunity to that illness. One of the more recent vaccinations, which is now accessible, is approved for the protection of monkeypox. Hexadecyloxypropyl-cidofovir (CDV) has superior oral bioavailability, less toxicity, and improved cellular penetration compared to CDV, administered intravenously. The European Medicines Agency authorized tecovirimat, an antiviral medicine developed to treat smallpox, to treat monkeypox in 2022 on the basis of data from both animal and human testing. It is still not readily accessible.

"Debordering" public health: the changing patterns of health border in modern Europe.

According to David Fidler, the governance of infectious diseases evolved from the mid-nineteenth to the twenty-first century as a series of institutional arrangements: the International Sanitary Regulations (non-interference and disease control at borders), the World Health Organization vertical programs (malaria and smallpox eradication campaigns), and a post-Westphalian regime standing beyond state-centrism and national interest. But can international public health be reduced to such a Westphalian image? We scrutinize three strategies that brought health borders into prominence: pre-empting weak states (eastern Mediterranean in the nineteenth century); preventing the spread of disease through nation-building (Macedonian public health system in the 1920s); and debordering the fight against epidemics (1920-1921 Russian-Polish war and the Warsaw 1922 Sanitary Conference).

EPPIC (Efficient Purification by Parental Inducer Constraint) Platform for Rapid Generation of Recombinant Vaccinia Viruses

Vaccinia virus (VACV) was successfully used as a vaccine in the smallpox eradication campaign. Since then, it has been widely used in the development of vaccine and therapeutic vectors. However, methods of generating and purifying recombinant VACVs (rVACVs) are often time-consuming, cumbersome, and in some cases require specialized cell lines or equipment. Here, we describe a novel EPPIC (Efficient Purification by Parental Inducer Constraint) platform for the rapid generation of rVACVs using a replication-inducible VACV (vIND) as a parental virus for homologous recombination. Purification of the rVACV from the parental vIND is achieved by two serial passages in the absence of inducer (i.e., parental inducer “constraint”) in standard laboratory cell lines, without the need for specialized equipment, within 1 week. We determined the optimal conditions for homologous recombination and serial purification and generated a suite of vIND parental viruses to facilitate customization of the platform. Importantly, the EPPIC platform can be adapted to rapidly generate replication-deficient and replication-competent rVACVs expressing vaccine or therapeutic antigens, with or without screening markers, by simple modifications to a DNA shuttle vector, thus allowing the rapid development, updating, and refinement of personalized or custom vaccines and therapeutic vectors in a matter of days.

Thomas J.Bollyky, Plagues and the Paradox of Progress: Why the World is Getting Healthier in Worrisome Ways. Cambridge, MA: The MIT Press. 280 p. $27.95.

Currently, Niger's GDP per capita is $393; in 1980 it was $419. Today, students in Niger average 5 years of schooling, the lowest in the world, and just $71 is spent on the average Nigerien's health each year. The government is weak and corrupt, the country has the world's second lowest Human Development Index, and it is surrounded by regions experiencing violent insurgences. Yet, compared to 25 years ago, its life expectancy of 61 is 14 years higher and its infant mortality rate more than 60 percent lower. Over the past decade, the death rate from HIV/AIDS has dropped over 60 percent, malnutrition by 35 percent, malaria by 27 percent, and diarrheal disease by 48 percent. Bollyky, the Director of Global Health at the Council of Foreign Relations, uses Niger's statistics to illustrate that control over infectious disease and child mortality no longer depends on state capacity or income level, factors that were central to the control of infectious disease in now developed countries. This disconnect, while a notable accomplishment, worries Bollyky. Millions of infants and children, that formerly would have died, have survived as global vaccination campaigns have virtually eradicated smallpox and measles. The global distribution of mosquito netting and oral rehydration kits has significantly reduced the incidence of malaria and diarrheal diseases. These survivors have matured, and many now find themselves living impoverished lives in countries with underdeveloped health care systems that lack the capability to deal with unprecedented increases in noncommunicable diseases. They flee, in large numbers, to rapidly growing cities with poor infrastructures and few productive jobs. For Bollyky, whether the recent remarkable control of infectious disease will end with tragedy or triumph is yet to be determined. Bollyky argues his case using historical and disease-specific narratives. Chapter 1 covers the history of infectious disease from premodern time, when more advanced countries tended to be more disease-ridden, to the modern era when wealth and public health advances reversed that relationship. Chapter 2 traces the 1950s smallpox and malaria eradication campaigns to their colonial and military roots, noting that these top-down technology-driven strategies, while producing dramatic results, required few fundamental changes in governments or economies. Chapter 3 looks at the recent control of childhood disease; effective vaccines for measles, mumps, and rubella were only developed in the 1960s. The ensuing dramatic declines in childhood diseases occurred very quickly and produced age structures with distinct “youth bulges.” Bollyky contrasts the success that China has had in securing its demographic dividend with Kenya's much more limited success. Chapter 4 examines the story of tuberculosis, cholera, and other intestinal diseases, ones that in the past had made cities dangerous places in which to live. These diseases can now be “frugally” controlled, but the result has been the explosive growth of “poor world cities,” such as Dhaka, where population growth has outpaced gains in access to clean water, adequate sanitation, and schools. Chapter 5 assesses the very recent international health campaigns that have targeted the diseases common to the world's poorest and most ecologically challenged countries: meningitis and other neglected infectious and parasitic diseases. Success here has produced growing cohorts of young adults for whom emigration seems to hold the only key to a positive future. Today less than 20 percent of the total death and disability in South Asia is caused by infectious diseases, and it is less than 44 percent in sub-Saharan Africa. By 2040, Bangladesh's health burden will look like that of the contemporary United States, dominated by cancer, heart disease, and other noncommunicable diseases. Bollyky contends that what will be needed to deal with this new health burden is much more than just a revamped health care system. What will be needed is freer trade, more rapid economic growth, a more inclusive educational system, and better governance.

Chronicle of a consolidated success: smallpox eradication policies in Brazil (1962-1973).

The aim of this article is to understand actions taken towards smallpox eradication in Brazil, in the framework of the Smallpox Eradication campaign that took place in the 1960s and 1970s. The article argues that, in addition to the bifurcated needle and the lyophilized vaccine, epidemiological surveillance - based on the construction of instruments and protocols for health surveillance - was the third key element that guaranteed the eradication of the disease. The hypothesis is that the actions taken towards the control and eradication of smallpox contributed to the construction of new health institutions within Brazil. As an exercise of socio-historical analysis, this research was based on documentary sources (reports, newsletters and legislation), interviews with professionals directly involved in the eradication of smallpox, and part of the intellectual production on the subject.

Progress in gene therapy using oncolytic vaccinia virus as vectors.

Vaccinia virus was widely used in the World Health Organization's smallpox eradication campaign and is currently a promising vector for gene therapy owing to its unique characteristics. Vaccinia virus can selectively replicate and propagate productively in tumor cells, resulting in oncolysis. In addition, rapid viral particle production, wide host range, large genome size (approximately 200 kb), and safe handling render vaccinia virus a suitable vector for gene therapy. Cancer vaccines and gene therapy are being studied in clinical trials and experiment researches. However, we put forward unique challenges of optimal selection of foreign genes, administration and modification of VACV, personalized medicine, and other existing problems, based on current researches and our own experiments. This review presents an overview of the vaccinia virus from its mechanisms to medical researches and clinical trials. We believe that the solution to these problems will contribute to understanding mechanisms of VACV and provide a theoretical basis for clinical treatment.

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

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.

Generation and Production of Modified Vaccinia Virus Ankara (MVA) as a Vaccine Vector.

The smallpox vaccine based on the vaccinia virus was successfully used to eradicate smallpox, but although very effective, it was a very reactogenic vaccine and responsible for the deaths of one to two people per million vaccinated. Modified Vaccinia virus Ankara (MVA) is an attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. MVA can encode one or more foreign antigens and thus can function as a multivalent vaccine. The vector can be used at biosafety level 1, has intrinsic adjuvant properties, and induces humoral and cellular immune responses. Many clinical trials of these new vaccines have been conducted, and the safety of MVA is now well documented. Immunogenicity is influenced by the dose and vaccination regimen, and information on the efficacy of MVA-vectored vaccines is now beginning to accumulate. In this chapter, we provide protocols for generation, isolation, amplification, and purification of recombinant MVA for preclinical and clinical evaluation.

Genome Sequence of Vaccinia virus Strain Lister-Butantan, a Lister Vaccine Variant Used during a Smallpox Eradication Campaign in Brazil.

Here, we report the 187.8-kb genome sequence of Vaccinia virus Lister-Butantan, which was used in Brazil during the WHO smallpox eradication campaign. Its genome showed an average similarity of 98.18% with the original Lister isolate, highlighting the low divergence among related Vaccinia virus vaccine strains, even after several passages in animals and cell culture.

From lesions to viral clones: biological and molecular diversity amongst autochthonous Brazilian vaccinia virus.

Vaccinia virus (VACV) has had an important role for humanity because of its use during the smallpox eradication campaign. VACV is the etiologic agent of the bovine vaccinia (BV), an emerging zoonosis that has been associated with economic, social, veterinary and public health problems, mainly in Brazil and India. Despite the current and historical VACV importance, there is little information about its circulation, prevalence, origins and maintenance in the environment, natural reservoirs and diversity. Brazilian VACV (VACV-BR) are grouped into at least two groups based on genetic and biological diversity: group 1 (G1) and group 2 (G2). In this study, we went to the field and investigated VACV clonal diversity directly from exanthemous lesions, during BV outbreaks. Our results demonstrate that the G1 VACV-BR were more frequently isolated. Furthermore, we were able to co-detect the two variants (G1 and G2) in the same sample. Molecular and biological analysis corroborated previous reports and confirmed the co-circulation of two VACV-BR lineages. The detected G2 clones presented exclusive genetic and biological markers, distinct to reference isolates, including VACV-Western Reserve. Two clones presented a mosaic profile, with both G1 and G2 features based on the molecular analysis of A56R, A26L and C23L genes. Indeed, some SNPs and INDELs in A56R nucleotide sequences were observed among clones of the same virus population, maybe as a result of an increased mutation rate in a mixed population. These results provide information about the diversity profile in VACV populations, highlighting its importance to VACV evolution and maintenance in the environment.

Vaccinia Virus in Household Environment during Bovine Vaccinia Outbreak, Brazil

Vaccinia Virus in Household Environment during Bovine Vaccinia Outbreak, Brazil

Mapping monkeypox transmission risk through time and space in the Congo Basin.

Monkeypox is a major public health concern in the Congo Basin area, with changing patterns of human case occurrences reported in recent years. Whether this trend results from better surveillance and detection methods, reduced proportions of vaccinated vs. non-vaccinated human populations, or changing environmental conditions remains unclear. Our objective is to examine potential correlations between environment and transmission of monkeypox events in the Congo Basin. We created ecological niche models based on human cases reported in the Congo Basin by the World Health Organization at the end of the smallpox eradication campaign, in relation to remotely-sensed Normalized Difference Vegetation Index datasets from the same time period. These models predicted independent spatial subsets of monkeypox occurrences with high confidence; models were then projected onto parallel environmental datasets for the 2000s to create present-day monkeypox suitability maps. Recent trends in human monkeypox infection are associated with broad environmental changes across the Congo Basin. Our results demonstrate that ecological niche models provide useful tools for identification of areas suitable for transmission, even for poorly-known diseases like monkeypox.

Genomic Sequence and Virulence of Clonal Isolates of Vaccinia Virus Tiantan, the Chinese Smallpox Vaccine Strain

Despite the worldwide eradication of smallpox in 1979, the potential bioterrorism threat from variola virus and the ongoing use of vaccinia virus (VACV) as a vector for vaccine development argue for continued research on VACV. In China, the VACV Tiantan strain (TT) was used in the smallpox eradication campaign. Its progeny strain is currently being used to develop a human immunodeficiency virus (HIV) vaccine. Here we sequenced the full genomes of five TT clones isolated by plaque purification from the TT (752-1) viral stock. Phylogenetic analysis with other commonly used VACV strains showed that TT (752-1) and its clones clustered and exhibited higher sequence diversity than that found in Dryvax clones. The ∼190 kbp genomes of TT appeared to encode 273 open reading frames (ORFs). ORFs located in the middle of the genome were more conserved than those located at the two termini, where many virulence and immunomodulation associated genes reside. Several patterns of nucleotide changes including point mutations, insertions and deletions were identified. The polymorphisms in seven virulence-associated proteins and six immunomodulation-related proteins were analyzed. We also investigated the neuro- and skin- virulence of TT clones in mice and rabbits, respectively. The TT clones exhibited significantly less virulence than the New York City Board of Health (NYCBH) strain, as evidenced by less extensive weight loss and morbidity in mice as well as produced smaller skin lesions and lower incidence of putrescence in rabbits. The complete genome sequences, ORF annotations, and phenotypic diversity yielded from this study aid our understanding of the Chinese historic TT strain and are useful for HIV vaccine projects employing TT as a vector.

Clinical development of Modified Vaccinia virus Ankara vaccines

The smallpox vaccine Vaccinia was successfully used to eradicate smallpox, but although very effective, it was a very reactogenic vaccine and responsible for the deaths of one or two people per million vaccinated. Modified Vaccinia virus Ankara (MVA) is a replication-deficient and attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. Many clinical trials of these new vaccines have been conducted, and the findings of these trials are reviewed here. The safety of MVA is now well documented, immunogenicity is influenced by the dose and vaccination regimen, and information on the efficacy of MVA-vectored vaccines is now beginning to accumulate.