Smallpox: Development and Use of the Panoply of Countermeasures in the Armamentarium

By Michael Krug

Smallpox remains one of the most devastating biothreats known to mankind. The reemergence of the variola virus, a member of the orthopoxvirus genus, could result in a catastrophic loss of life worldwide due to high transmissibility and high mortality rates, in combination with a relatively immunologically naive human population. The development of a safer and better tolerated vaccine would greatly ease the threat of a smallpox reemergence. The development of a new medical countermeasure (MCM) is easier said than done. The absence of the disease makes research and development a very difficult task. This session, moderated by BARDA’s Michael Merchlinsky, sought to provide detail into some of the recent breakthroughs throughout the orthopoxvirus field.

The first presenter of this session was Dr. Paul Chaplin of Bavarian Nordic. His presentation, titled The Approval of JYNNEOS, an Attenuated MVA-Based Vaccine for the Prevention of Smallpox and Monkeypox Infections, provided detail on the progression of developing an MCM without the luxury of working with the disease. Due to the harsh complications, especially to high risk individuals, that the traditional smallpox vaccines could cause, the U.S. government sought to develop a safer vaccine. In 2018, after nearly 15 years of public-private partnership efforts between BARDA and Bavarian Nordic, the U.S. FDA approved JYNNEOS for prevention of smallpox and monkeypox. The vaccine is a further attenuated version of the Modified Vaccinia Ankara (MVA) virus. JYNNEOS is unique because it is the first non-replicating smallpox vaccine to hit the market, greatly diminishing potential complications caused by replicating vaccines. When compared to the ACAM 2000, JYNNEOS stimulated an almost two-fold increase in antibody titer. Additionally, with greater than 10,500 clinical subjects, JYNNEOS has been proven to be safe and well tolerated, with no signs of clinical adverse side effects. JYNNEOS’s name was derived from Edward Jenner, the developer of the original smallpox vaccination process, known as scarification, and NEOS meaning new in Latin.

Second to present was Dr. Victoria Olson of the CDC. Dr. Olson’s presentation, titled Protecting Americans from the Unthinkable – Laboratory Investigations Advancing Smallpox Medical Countermeasures, which spoke to the important tasks of developing, testing, and verifying smallpox diagnostic tools, antivirals, and vaccines.Her lab is one of two in the world authorized to work with the smallpox virus, in case of a smallpox or smallpox-like disease release. A main point in Dr. Olson’s presentation focused on improving key smallpox diagnostic tests. Due to breakthroughs in the field and improvements across biotechnologies as a whole, smallpox detection and diagnostic methods constantly require updating from old reagents and equipment. The two current diagnostic methods involve a nucleic acid-based test, utilizing a multiplexed variola virus specific assay on the GeneXpert platform, and a protein-based test, using a human-specific IgG ELISA. The second part of Dr. Olson’s presentation focused on the complications surrounding testing the efficacy of vaccines and antivirals. Since variola virus solely infects humans, it makes it difficult to find viable animal models for testing. Currently, the CDC is looking to license the Plaque Reduction Neutralization Test (PRNT) for testing smallpox vaccine efficacy. For antivirals, her lab recently began developing a humanized mouse for variola virus infections. The characterization and validation continue, but early results were promising. Altogether this variola virus work requires the utmost precision and safety principles, often slowing down this novel and imperative research.

The final presenter was Dr. Brett Peterson of the CDC. His presentation, titled Vaccinating against Monkeypox in the Democratic Republic of the Congo (DRC), examined the CDC’s novel monkeypox vaccination program. Monkeypox, a disease that presents very similarly to smallpox, has become endemic in the DRC. The disease is contracted from animal vectors and can have limited human-to-human transmissibility, with a R₀ of less than 1. The CDC has started enhanced surveillance within the DRC, in order to identify key weaknesses that aid in the spread of the monkeypox virus. Dr. Peterson identified several gaps that included inadequate medical facilities, increased human-to-human transmission because of improper personal protective equipment (PPE), and substandard hand hygiene. While good preventive practices were taught and emulated, the monkeypox disease continued to spread throughout Central and West Africa. Dr. Peterson’s team noticed an opportunity to evaluate smallpox vaccines in the presence of a natural orthopoxvirus disease. In collaboration with the DRC Ministry of Health and the Kinshasa School of Public Health, the CDC developed an investigational new drug protocol investigating the safety and efficacy of JYNNEOS in individuals at-risk of being infected by the monkeypox virus.  The JYNNEOS vaccine was administered to study participants on days 0 and 28. The study participants were then asked to return for blood draws on day 0, 14, 28, 42, 180, as well as 1 year, 1.5 years, and 2 years after the vaccine was administered. Each participant was also asked to keep a diary on adverse effects as a record of all complications. With over 7000 individuals participating in the study, the results were overwhelmingly positive. No vaccine-associated adverse events were reported and no monkeypox sicknesses identified in the vaccinated cohorts. This novel study provided detailed evidence that orthoxpovirus vaccines can be used across species.

Variola virus research can often be stigmatized since the disease was eradicated in 1980; however, the risk of potential bioterrorism, even after eradication, supports continued research, especially for the session participants mentioned above. Additionally, as viruses become cheaper and easier to synthesize from scratch, this research could be used at the frontlines against a nefarious release of synthesized variola virus. Preventive measures, diagnostic tools, and therapeutics can alleviate the threat of smallpox reemergence and the consequence of other orthopoxviruses.