Safety Testing Critical for COVID-19 Therapies and Vaccines

As COVID-19 deaths rise and the world economy continues to take devastating hits, countries, states, and cities are desperate for anything that can provide relief. Dr. Jiang, professor of virology at Fudan University, notes that, "combating this disease demands a vaccine that is safe and potent. The fatality rate is low (3.4% by the World Health Organization's latest estimate, although this is highly uncertain), yet transmission rates are high and the spread is difficult to track. That means many people -- perhaps the majority in hotspots -- would need to be vaccinated to stop the spread and prevent deaths."¹

Dr. Jiang has worked to develop vaccines and treatments for coronaviruses since 2003, when the severe acute respiratory syndrome (SARS) outbreak happened. He believes, "standard protocols are essential for safeguarding health. Before allowing use of a COVID-19 vaccine in humans, regulators should evaluate safety with a range of virus strains and in more than one animal model. They should also demand strong preclinical evidence that the experimental vaccines prevent infection, even though that will probably mean waiting weeks or even months for the models to become available."¹

Safety assessment of therapies and vaccines

(Photo credit Leonard McCombe/Time Life Pictures/Getty Images)

The importance of safe vaccines and drugs cannot be overemphasized. History is rife with examples of catastrophic "adverse events" from treatments that were not fully assessed for safety. A possible side effect resulting from a vaccination or drug treatment is known as an adverse event.

Perhaps the most well-known unanticipated treatment side effect is the horrifying results of the drug thalidomide that was prescribed for nausea in pregnant women and as a sedative.

More than 10,000 children in the 1960's, like the kindergartner in the image, were born with phocomelia as a side effect of thalidomide, resulting in the shortening or absence of limbs.

The tragedy surrounding thalidomide helped motivate profound changes in the FDA by passing the Kefauver-Harris Drug Amendments Act in 1962 and is the basis for the extensive drug safety testing required today.

Vaccine Safety

While birth defects are an extreme example of safety problems with therapies, the following are known "adverse events" in the Mild to Severe² categories of vaccine side effects:

• Mild rash, lasting 2-4 days
• Swelling and tenderness of lymph nodes, lasting 2-4 weeks after the blister has healed
• Fever of over 100°F (about 70% of children, 17% of adults) or over 102°F (about 15%-20% of children, under 2% of adults)
• Secondary blister elsewhere on the body (about 1 per 1,900)
• Serious eye infection, or loss of vision, due to spread of vaccine virus to the eye
• Rash on entire body (as many as 1 per 4,000)
• Severe rash on people with eczema (as many as 1 per 26,000)
• Encephalitis (severe brain reaction), which can lead to permanent brain damage (as many as 1 per 83,000)
• Severe infection beginning at the vaccination site (as many as 1 per 667,000, mostly in people with weakened immune systems)
• Death (1-2 per million, mostly in people with weakened immune systems)

Vaccine safety testing in animals is well established with antibiotic treatments and vaccines for leprosy being developed using armadillos then given to humans in the early 1970s³. Current vaccines for measles, mumps, rubella, polio, smallpox and influenza have a long history of safe use and were developed in line with requirements of regulatory agencies.

One concern with COVID-19 vaccines is immune enhancement, in which a vaccinated host develops more severe disease than an unvaccinated host. This can occur via several different immune mechanisms⁴. Rushing to roll out an unproven vaccine which actually makes the disease worse must be avoided, with both efficacy and safety proven through proper preclinical and clinical testing prior to broad usage.

Dr. Jiang notes that "around the world, I am seeing efforts to support 'quick-fix' programmes aimed at developing vaccines and therapeutics against COVID-19. Groups in the United States and China are already planning to test vaccines in healthy human volunteers. Make no mistake, it's essential that we work as hard and fast as possible to develop drugs and vaccines that are widely available across the world. But it is important not to cut corners. That is time well spent. Work with the SARS virus shows that worrying immune responses were seen in ferrets and monkeys, but not in mice. Also, some viral protein fragments can elicit more potent or less risky immune responses than others, and it makes sense to learn this in animal studies before trying them in people. Regulators must continue to require that vaccine developers check for potentially harmful responses in animal studies."¹

Dr. Jiang is worried that the urgency may elicit shortcuts in vaccine safety and development. He notes that China, The United States, and others are advancing several COVID-19 vaccines of different types, and China has announced plans to have products in human tests or emergency use in healthy people as early as late April. He is also concerned with agencies approving a myriad of other drugs that are currently approved for other diseases, but not specifically tested for coronavirus. There is a risk these drugs can also have unanticipated adverse events when used in combination with other drugs.

Drug Safety

Small molecule drugs including antiviral therapies must pass a rigorous program of preclinical safety tests before regulatory approval. Standard preclinical testing is designed to identify toxic effects from acute and chronic administration as well as identify potential safety issues with combination therapies. Side effects can result from changes in metabolism/transport of one drug (particularly those with a narrow therapeutic index) caused by interaction of another drug with drug transporter proteins or cytochrome P450s. Many of these safety studies occur relatively early in the drug development process. While most of these assays are performed in standard inbred and outbred mouse and rat strains, transgenic mice (knockout or genetically humanized) are sometimes used to investigate specific questions.

One of the final preclinical safety studies often occurs concurrent with clinical-phase testing. Carcinogenicity testing is designed to discover whether drugs, particularly those administered over a long timeframe, can induce tumor formation. Although the traditional way to perform this testing involved lifetime administration (2 years) of a compound to a mouse, use of a transgenic model such as the rasH2™ mouse can reduce this to just 6 months. Given that some of the drugs currently been studies for efficacy against COVID-19 such as remdesivr are investigational compounds not yet approved by regulatory agencies, faster ways to identify safety concerns are invaluable.

There are many well established animal models for efficacy and safety testing of vaccines and drugs, with many more that are rapidly emerging. Taconic has taken a proactive role in providing relevant animal models to researchers engaged in the fight against COVID-19. Check out Taconic's Coronavirus (COVID-19) Tookit, a fantastic resource for investigators studying this disease.

References:

1. Jiang, Shibo, "Don't rush to deploy COVID-19 vaccines and drugs without sufficient safety guarantees", Nature, World View, 16 March 2020.
2. https://www.historyofvaccines.org/content/articles/vaccine-side-effects-and-adverse-events.
3. Scollard DM, Adams LB, Gillis TP, Krahenbuhl JL, Truman RW, Williams DL (2006). "The Continuing Challenges of Leprosy". Clin. Microbiol. Rev. 19 (2): 338-81. doi:10.1128/CMR.19.2.338-381.2006. PMC 1471987. PMID 16614253.
4. Peeples, L. News Feature: Avoiding pitfalls in the pursuit of a COVID-19 vaccine. Proceedings of the National Academy of Sciences April 2020, 117 (15) 8218-8221; DOI: 10.1073/pnas.2005456117