MicrobiologyBytes

At the 64th gathering of the World Health Assembly in May 2011, a majority of delegates reaffirmed the view that the remaining stocks of variola virus, the causative agent of smallpox, should be destroyed. But consideration of precisely when that action should be taken was postponed for several years pending completion of crucial research addressing the development and assessment of tools for the treatment and control of the disease should it ever reoccur. This agenda of research includes the development and testing of vaccines and therapeutics, at the heart of which involves understanding the mechanisms that govern variola’s virulence and its capability to evade host defenses. But how can these questions be addressed when naturally occurring disease has been eliminated and no satisfactory animal model exists?

In the absence of smallpox, human infections with monkeypox virus constitute the most significant communicable Orthopoxvirus-associated illnesses extant in the world today. Monkeypox is not a direct research-proxy or substitute for smallpox (monkeypox is a zoonosis that can affect a broad range of animal taxa, whereas smallpox was an exclusive disease of humans) but vaccines and therapies developed for smallpox may be useful for the prevention and treatment of monkeypox, and many of the cornerstones of pathogenesis and immunomodulation for both variola and monkeypox probably emanate from conserved homologous processes. Both variola and monkeypox viruses are considered threat agents that could be used unlawfully for acts of bioterrorism. With monkeypox, there is the added question of its persistence in nature, and its potential for expansion in a world that is now more than 30 years without smallpox. A significant expansion of monkeypox in the world today could pose many of the same challenges as a resurgence of smallpox.

Outbreaks of human monkeypox after cessation of smallpox vaccination. Trends Microbiol. 10 Jan 2012
The recent observation of a surge in human monkeypox in the Democratic Republic of the Congo (DRC) prompts the question of whether cessation of smallpox vaccination is driving the phenomenon, and if so, why is re-emergence not universal throughout the historic geographic range of the virus? Research addressing the virus’s mechanisms for immune evasion and induction, as well as that directed at elucidating the genes involved in pathogenesis in different viral lineages (West African vs Congo Basin), provide insights to help explain why emergence appears to be geographically limited. Novel vaccines offer one solution to curtail the spread of this disease.

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Recent evidence shows that the quadrivalent HPV vaccine prevents several HPV-related diseases in men. However, despite the licensure of the vaccine in the USA for men 9 through 26 years of age, rates of male vaccination are very low. Research on acceptability, in general, indicates strong interest in vaccination among men, parents, and healthcare providers, though female vaccination is typically seen as a higher priority. Cost-effectiveness studies indicate that in the context of modest female vaccination rates and with the specification of a broad range of disease outcomes (e.g. genital warts, anogenital cancers, and oropharyngeal cancers), male vaccination can be quite cost-effective.

This review describes the indications for vaccinating men with the quadrivalent human papillomavirus (HPV) vaccine, reports on the U.S. rates of male vaccination, and reviews the recent research on acceptability of vaccinating men and research on the cost-effectiveness of adding men to existing female HPV immunization programs.

Summary: Men are at high risk for HPV infection and can benefit from vaccination, but vaccination rates among men remain extremely low. More research needs to be done on the predictors of uptake of HPV vaccine among men and on the development of interventions to increase male vaccination.

Human papillomavirus vaccine and men: what are the obstacles and challenges? (2012) Curr Opin Infect Dis. 25(1): 86-91

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First it was foot and mouth virus.
Then it was bluetongue virus.
Now it is Schmallenberg virus.
So here’s 10 things you didn’t know about Schmallenberg virus:

1. Schmallenberg virus was first isolated in Schmallenberg, Germany, in November 2011.
2. Schmallenberg virus is a Bunyavirus, one of a large group of of negative-stranded RNA viruses.
3. Why should I care? In cows, Schmallenberg virus causes fever and a drastic reduction in milk production. In sheep it causes congenital malformations and stillborn lambs (also stillborn calves in cows).
4. Schmallenberg virus was first identifed in the UK on 23rd January 2012.
5. Like Bluetongue, Schmallenberg virus is transmitted by midges (Culicoides spp.), which means we will be unlikely to be able to eradicate it – vaccination of anaimals is the only likely effective response.
6. Where did Schmallenberg virus come from? The virus genome is most closely related to sequences of a different Orthobunyavirus called Shamonda virus which belongs to the so-called Simbu serogroup known to infect ruminants and be transmitted by midges. In other words, it has form. But whether it is newly evolved (unlikely) or just newly discovered we don’t yet know.
7. How did Schmallenberg virus reach the UK? We don’t know. It could have been due to animal movements, but since it was first identifed in eastern England, it’s possible that it arrived in midges travelling under their own steam.
8. Is Schmallenberg virus going to spread to other parts of the UK and other countries? Yes, you can bet on that (just like bluetongue did).
9. Can I catch Schmallenberg virus? Honest answer: We don’t know. Possibly, but there have been no reports of human illness from areas where the virus is known to exist, so I wouldn’t worry too much.
10. Where can I find the latest news about Schmallenberg virus? Right here.
11. OK, one last time, why should I care? Because Schmallenberg virus is going to cost European and probably worldwide ecomonies millions of pounds. And that will affect you.

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It was my privilege to work with Phil Minor during my PhD. 25 years later (gulp), Phil looks back and forward to the polio endgame.

The Polio-Eradication programme and issues of the end game. J Gen Virol. Nov 29 2011
Poliovirus causes paralytic poliomyelitis, an ancient disease of humans that became a major public health issue in the 20th century. The primary site of infection is the gut where virus replication is entirely harmless; the two very effective vaccines developed in the 1950s (Oral Polio Vaccine, or OPV and Inactivated Polio Vaccine, or IPV) induce humoral immunity which prevents viraemic spread and disease. The success of vaccination in developing countries and in middle income countries encouraged the World Health Organization to commit itself to an eradication programme which has made great advances. The features of the infection including its largely silent nature and the ability of the live vaccine (OPV) to evolve and change in vaccine recipients and their contacts make eradication particularly challenging. Understanding the pathogenesis and virology of the infections is of major significance as the programme reaches its conclusion.

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Cowpox virus (CPXV) is one of the earliest described members of the genus Orthopoxvirus (OPV). Historically, researchers referred to the ailment known as cowpox and even suggested that it could provide immunity against smallpox. It was Edward Jenner’s publications in 1798 and 1799 which provided the first scientific description of vaccination by detailing the efficacy of CPXV “scarification” in inducing protective immunity against challenge with variola (smallpox) virus (VARV). The common name “cowpox virus” refers to the association with pustular lesions on the teats of cows and historic zoonotic transmission of this disease to humans (milkers) through contact with infected cows. Human infections are generally mild and self-limiting with localized skin lesions healing after 3–4 weeks, however, systemic involvement and fatal outcome have been reported in immunocompromised individuals.

New analysis shows that the smallpox vaccine is known to have originated in the United Kingdom, however the vaccine strains were most closely allied to CPXV isolates from Russia and from Finland. The most likely scenario is that most of the commercially produced smallpox vaccines were not made from the original Jenner strain, but instead from isolates found in other regions of Europe.

Chasing Jenner’s Vaccine: Revisiting Cowpox Virus Classification. (2011) PLoS ONE 6(8): e23086. doi:10.1371/journal.pone.0023086
Cowpox virus (CPXV) is described as the source of the first vaccine used to prevent the onset and spread of an infectious disease. It is one of the earliest described members of the genus Orthopoxvirus, which includes the viruses that cause smallpox and monkeypox in humans. Both the historic and current literature describe “cowpox” as a disease with a single etiologic agent. Genotypic data presented herein indicate that CPXV is not a single species, but a composite of several (up to 5) species that can infect cows, humans, and other animals. The practice of naming agents after the host in which the resultant disease manifests obfuscates the true taxonomic relationships of “cowpox” isolates. These data support the elevation of as many as four new species within the traditional “cowpox” group and suggest that both wild and modern vaccine strains of Vaccinia virus are most closely related to CPXV of continental Europe rather than the United Kingdom, the homeland of the vaccine.

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It seems like only yesterday we were on the verge of international agreement to destroy all remaing laboratory stocks of smallpox (variola) virus. So it comes as something of a surprise to find people infecting monkeys with smallpox to study the pathogenesis of the disease. Such studies significantly advance our understanding of variola pathogenesis in primates and could help development of new antiviral drugs, improved bioterrorism countermeasures, and suggest new potential targets for therapeutic intervention in humans.

But is it a good idea?

Progression of Pathogenic Events in Cynomolgus Macaques Infected with Variola Virus. (2011) PLoS ONE 6(10): e24832. doi:10.1371/journal.pone.0024832
Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of antivirals and improved vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary smallpox model, lymphoid and myeloid hyperplasias were consistently found whereas lymphocytolysis and hematopoietic necrosis developed in hemorrhagic smallpox. Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary smallpox model. In contrast, in the hemorrhagic model antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic smallpox developed only in the presence of secondary bacterial infections – an observation also commonly noted in historical reports of human smallpox. Together, our results support the macaque model as an excellent surrogate for human smallpox in terms of disease onset, acute disease course, and gross and histopathological lesions.

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A number of flaviviruses constitute a significant threat to global health. Dengue virus (DENV) infection causes around 21,000 human deaths annually, and it is estimated that at least 120 countries have endemic DENV transmission, whilst in recent years, West Nile virus (WNV) has become more prominent as a zoonotic agent, particularly in North America where the virus first emerged in 1999 and rapidly spread across the continent. WNV has now emerged in a number of European countries, particularly around the Mediterranean basin, where infections in humans, horses and birds have been reported.

Cross-reactivity of sera raised against one flavivirus recognising another flavivirus has been well documented. One consequence of flavivirus cross-reactivity is the occurrence of false-positive results, yet cross-reactivity can lead to cross-protection. Understanding and manipulating the cross-reactive properties of flaviviruses has the potential to assist the development of effective broad-spectrum human vaccines against WNV and other existing and emerging flaviviruses.

Flavivirus-induced antibody cross-reactivity. J Gen Virol. Sep 7 2011
Dengue viruses (DENV) cause countless human deaths each year, whilst West Nile virus (WNV) has re-emerged as an important human pathogen. There are currently no WNV or DENV vaccines licensed for human use, yet vaccines exist against other flaviviruses. To investigate flavivirus cross-reactivity, sera from a human cohort with a history of vaccination against tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV) and yellow fever virus (YFV) were tested for antibodies by plaque reduction neutralisation test. Neutralisation of Louping ill virus (LIV) occurred, but no significant neutralisation of Murray Valley encephalitis virus (MVEV) was observed. Sera from some individuals vaccinated against TBEV and JEV neutralised WNV, which was enhanced by YFV vaccination in some recipients. Similarly, some individuals neutralised DENV-2, but this was not significantly influenced by YFV vaccination. Antigenic cartography techniques were used to generate a geometric illustration of the neutralisation titres of selected sera against WNV, TBEV, JEV, LIV, YFV and DENV-2. This demonstrated the individual variation in antibody responses. Most sera had detectable titres against LIV and some had titres against WNV and DENV-2. Generally, LIV titres were similar to titres against TBEV, confirming the close antigenic relationship between TBEV and LIV. JEV was also antigenically closer to TBEV than WNV, using these sera. The use of sera from individuals vaccinated against multiple pathogens is unique relative to previous applications of antigenic cartography techniques. It is evident from these data that notable differences exists between amino acid sequence identity and mapped antigenic relationships within the family Flaviviridae.

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Researchers have developed a single vaccine which protects against both rabies and Ebola virus. These two viruses are related to each other, but do not cross-react serologically. By inserting elements of the Ebola virus GP protein into an existing rabies virus vaccine, a single bivalent vaccine was produced. Although it works in the laboratory, the new vaccine – or something similar based on this first attempt – need to be tested in primates and eventually in humans.

Apart from people, Ebola virus is thought to have eradicated thousands of gorillas, prompting the World Conservation Union to raise their status to “critically endangered” in 2007, the first time a mammal has become critically endangered as a direct result of disease. Vaccination could help prevent future deaths.

Inactivated or Live-Attenuated Bivalent Vaccines that Confer Protection against Rabies and Ebola Viruses. J Virol. Aug 17 2011
The search for a safe and efficacious vaccine for Ebola virus continues as no current vaccine candidate is nearing licensure. We have developed (a) replication-competent, (b) replication-deficient, and (c) chemically inactivated rabies virus (RABV) vaccines expressing Zaire ebolavirus (ZEBOV) glycoprotein (GP) using a reverse genetics system based on the SAD B19 RABV wildlife vaccine. ZEBOV GP is efficiently expressed by these vaccine candidates and is incorporated into virions. The vaccine candidates were avirulent after inoculation of adult mice, and viruses with a deletion in the RABV glycoprotein have greatly reduced neurovirulence after intracerebral inoculation in suckling mice. Immunization with live or inactivated RABV vaccines expressing ZEBOV GP induced humoral immunity against each virus and conferred protection from both lethal RABV and EBOV challenge in mice. The bivalent RABV/ZEBOV vaccines described here have several distinct advantages that may speed the development of inactivated vaccines for use in humans and potentially live or inactivated vaccines for endemic nonhuman primates at risk of EBOV infection.

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“In the 1990s, experts thought they were close to eliminating measles for good. But now the World Health Organization (WHO) has put back its target date for getting rid of the disease to 2015. But even that seems unlikely. The reason? A measles outbreak which is spreading across Europe, affecting France, Belgium, Germany and Romania – and now the UK…”

Read more: BBC News – Measles outbreak warning as cases rise in Europe and UK