Will Smallpox Research Help in the Treatment of Monkeypox?

Author: AcceGen R&D Team

The current round of global monkeypox outbreaks has made the field of poxviruses a hot spot, and smallpox, a poxvirus, has become a good reference object.

What is Smallpox?

Smallpox is a severe infectious disease caused by the Variola virus (VARV, Figure.1). It is one of the most destructive infectious diseases known to humanity and is responsible for 10% of global deaths in the past thousand years, an estimated 400-500 million people died in the 20th century alone[1, 2]. The destruction of smallpox is mainly due to its high infectivity and mortality, as well as severe sequelae. It causes mortality rates of up to 30%, with higher infant and child mortality rates, and the survivors are often left with extensive permanent scarring and, in more severe cases, permanent blindness[3, 4]. And with the invention of the vaccinia vaccine and widespread vaccination, the millennium-long epidemic of smallpox was declared over by the WHO in 1980[2].

Timeline of the Global Smallpox Epidemic

The clinical records of smallpox can be traced back to ancient India and China more than 3000 years ago, and records of smallpox-like diseases can be found in some ancient medical works. Smallpox-like manifestations have also been found in a study of the Egyptian mummy of Ramses V, who died more than 3000 years ago[5, 6]. And there are also speculations that the spread of smallpox in history was from Egypt to India by Egyptian traders in the 1st millennium BCE, from India to China in the 1st century CE, and then from China to Japan in the 6^th century CE. There is no precise record of when smallpox spread into Europe, the most probable research evidence is that it was introduced by the Arabs in the 7th century. With the Crusades in the 11^th century, smallpox spread throughout Europe[7]. And up to the 16^th century, smallpox had become entrenched throughout Europe, and as European colonial expansion gradually spread into a global pandemic, killing large numbers of populations and significantly affecting the course of history[8].

How was smallpox wiped out?

The eradication of smallpox mainly depends on the vaccine, the earliest clear reference is Douzhen xinfa published in 1549 by Chinese author Wan Quan, the inoculation method is documented even as far back as the 10th century AD. Powdered smallpox scabs were blown into the noses of healthy people so that these people get a mild disease and become immune. Although the mortality rate of the vaccination is still 0.5%-2%, it is far lower than the average mortality rate of 30% of the sick[9]. This method was introduced to Europe in the form of reports in the 18th century and contributed to the history of subsequent vaccine eradication of smallpox[10]. The moment that directly contributed to the end of the millennium pandemic of smallpox was the observation of the resistance of milkmaids to smallpox by British doctors Edward Jenner. He demonstrated the effectiveness of cowpox in protecting people from smallpox in 1796, and then the vaccinia vaccination as a method of vaccination spread worldwide[11]. Smallpox eradication was first accomplished in North America (1952) and Europe (1953), but cases persist in other parts of the world. WHO launched a global smallpox eradication program in 1959 but went very poorly due to a lack of funding, personnel, and poor international cooperation. After the intensive eradication program began in 1967, smallpox eradication was completed in South America (1971), Asia (1975, the last person in the world infected with variola major), and Africa (1977, the last person in the world infected with variola minor). And the last patient to die from smallpox was a medical photographer at a smallpox-related research facility (Janet Parker, England’s Birmingham University Medical School).[7].

After the smallpox epidemic was completely ended, it turned into a biosecurity issue. The safety of strain storage and research, and even easier strain reconstruction as technology advances, is a risk that needs to be avoided[12, 13].

Clinical features and diagnosis

Smallpox is mainly transmitted through the respiratory tract, with a higher transmission rate caused by aerosols. And contact with skin and body fluids is also a route of infection for smallpox[14]. Early symptoms of infection are similar to some conventional diseases (such as common cold or flu), including fever (above 38.3°C), muscle pain, headache, fatigue, etc. And due to the infection, gastrointestinal symptoms such as vomiting will occur. Early symptoms usually last 2-4 days, and 12 to 15 days after the onset of symptoms, the skin symptoms appear as red spots, and as the symptoms progress rapidly, the skin symptoms rapidly expand and rupture, and the virus is released in large quantities[15].

Smallpox can be divided into Variola major and Variola minor. Variola major is the majority that causes more serious illnesses (such as confluent smallpox) and up to 30% mortality. Variola minor is an uncommon form with mild symptoms and a documented mortality rate of less than 1%[16]. In addition, there are two rare and very dangerous outbreaks of smallpox, malignant-type smallpox, and Hemorrhagic smallpox. The proportion of Malignant-type smallpox (also called flat smallpox) is about 5%-10%, and it is mainly in children (72%). Its early symptoms and skin symptoms are very violent, and the high mortality rate makes it very deadly[8]. Hemorrhagic smallpox is a more serious form, accounting for about 2%. It will lead to extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and viscera, and this form is also referred to as variola nigra or “black pox.”, the patient’s chances of survival are very low[17].

Significance of Smallpox Research Today

Smallpox research has remained a non-hot spot for many years since its complete end a few decades ago, and has largely focused on biosafety and ethics. However, the current round of global monkeypox outbreaks has made the field of poxviruses a hot spot, and smallpox, a poxvirus, has become a good reference object. Therefore, it will become more practical to review, summarize and analyze the history, epidemiological prevention, clinical manifestations, diagnosis, and treatment of smallpox.

References

1. Thèves C, Biagini P, Crubézy E: The rediscovery of smallpox. Clin Microbiol Infect 2014, 20:210-218.

2. (WHO) WHO: Smallpox. https://wwwwhoint/health-topics/smallpox#tab=tab_1.

3. CDC: What is Smallpox? 2016.

4. Riedel S: Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent) 2005, 18:21-25.

5. Shelton HM: Vaccine and Serum Evils.

6. DR H: The Greatest Killer: Smallpox in history. University of Chicago Press; 2002.

7. CDC.gov: Smallpox. https://wwwcdcgov/smallpox/history/historyhtml.

8. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID, World Health O: Smallpox and its eradication / F. Fenner … [et al.]. Geneva: World Health Organization; 1988.

9. J N: Part 6, Medicine. In Science and Civilization in China: Volume 6, Biology and Biological Technology. Cambridge: Cambridge University Press; 1999

10. AM S: A History of Immunology (2nd ed.). Academic Press; 2009.

11. Wolfe RM, Sharp LK: Anti-vaccinationists past and present. Bmj 2002, 325:430-432.

12. Noyce RS, Lederman S, Evans DH: Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments. PLoS One 2018, 13:e0188453.

13. NPR.org: Russian Lab Explosion Raises Question: Should Smallpox Virus Be Kept Or Destroyed?

14. Meyer H, Ehmann R, Smith GL: Smallpox in the Post-Eradication Era. Viruses 2020, 12.

15. Smallpox. In Armed Forces Institute of Pathology: Department of Infectious and Parasitic Diseases. 2008