05/27/20
At a time when so many lives across the world have been lost to the invisible viral threat called coronavirus or SARS-COV-02, the exit strategy for nearly every country is focused squarely on a vaccine being developed.
Here, we consider why vaccine candidates require testing with animals before human trials can be conducted. We review three scientific papers that have caught the attention of the media (also here). These papers are on important developments to fight the coronavirus based on research with mice and in large part with monkeys.
The small number of mice and monkeys in the studies have contributed to a Phase I human clinical trial that started on April 23, 2020 and as of May 13, 2020 has had more than 1000 human volunteers. This clinical trial has the possibility of determining whether this vaccine candidate could help millions, or if others need to be assessed. The other two papers that we consider further below are testing other vaccine candidates that appear to be going to human clinical trials later this year (September, 2020). In the current situation, all of these strategies and maybe more will need to be assessed and depend on research with monkeys.
What is a vaccine and why is safety testing in animals necessary?
Vaccines are either killed viruses or particles that resemble the virus but would not cause disease. They are typically injected into the body to allow it to develop an immune response. However, the body could react very strongly to the vaccine or when the virus is detected. Thus, efficacy and safety testing is crucial before a good vaccine candidate is found. Speaking of Research has more information on vaccines and the importance that animal research plays, here.
What did the first animal research study show?
We will first consider the preprint study in more detail because it has not yet been scientifically peer reviewed. The preprint of the paper was recently uploaded by the scientific group to BioRxiv, a scientific paper preprint service where papers can be read as they are scientifically reviewed. This study’s results have already informed a human clinical trial underway.
The study by Doremalen and colleagues aimed to assess whether a potential vaccine candidate (ChAdOx1 nCoV-19) causes severe side effects, such as, pneumonia. The study was conducted in collaboration between scientists in the US (Laboratory of Virology and Rocky Mountain Veterinary Branch of the National Institute of Allergy and Infectious Diseases) and UK (Jenner Institute at the University of Oxford). The group’s results are promising.
The study is based on prior research in chimpanzees during the Middle East Respiratory Syndrome (MERS) epidemic a few years ago, where a vaccine developed in apes was subsequently able to protect monkeys from developing this severe respiratory disorder.
Without this candidate vaccine developed during the prior epidemic with apes and monkeys, the evaluation of a vaccine candidate for coronavirus (SARS-COV-02) by this study would likely not have been possible or would have required a much longer time to develop.
The scientists modified the vaccine so that it contained the spiky protein of the coronavirus that many of us have seen in pictures of the coronavirus (SARS-COV-02).
This protein could act to encourage the body to develop an immune response, but because it does not include the disease bearing virus (RNA) components required for the virus to replicate in its host cell, it is not going to cause the disease.
That all sounds good in practice, but previous experience has suggested that there are potential dangers. For example, the body could react severely and adversely to the new bioengineered construct, and it could fail to develop an immune response to protect against the coronavirus. Or, the next time the body is exposed to the actual virus the immune system could go into overdrive, which may be worse than the reported mild-to-moderate symptoms of the disease.
The researchers started by relying on two strains of mice. Thirteen mice in total were studied (strains BALB and C57, different strains from others that Speaking of Research has discussed here) to see if the body would develop an immune response to the potential vaccine. The immune response was assessed 9-14 days later, and all mice showed antibodies against SARS-COV-02.
Next, the scientists studied monkeys (rhesus macaques) because, like humans, monkeys are also affected by the coronavirus and show respiratory problems. Thus, the work in monkeys was necessary and could not be taken further with the mice.
For this vaccine study, six macaque monkeys were vaccinated, half of them with half of the dose currently being assessed with vaccines in human trials and the others with the full dose. These six animals were compared to 3 control monkeys that did not receive any vaccine. Antibodies against the virus were detected as early as 14 days later in both groups of vaccinated animals, but not in animals that were not vaccinated.
After the monkeys were vaccinated and given a chance to develop an immune response to the vaccine, they were then challenged with the virus. While all control animals showed increased breathing responses (an early sign of the disease), only 3 out of the 6 vaccinated animals did. Also, the control animals were shedding the virus 3 to 5 days after the abnormal breathing symptoms, but this was the case for only 2 of the vaccinated animals, raising the possibility that the vaccine reduced the severity of the disease and suppressed virus generation.
The study was completed 7 days after the viral infection to determine if the vaccine resulted in any lung pathology. None of the vaccinated animals developed lung pathology. But 2 out of 3 of the control animals had signs of pneumonia. Additionally, lung tissue from the control animals had much more virus than that of the vaccinated animals.
However, as important as this may seem, the paper is made available through a paper preprint service while it undergoes scientific peer review. Thus, the study still needs to be reviewed by scientists to ensure that it is robust, although there is already indication from scientists by way of quotes from scientists in the NBC News article that the work is sound.
If this is promising, why is more research with monkeys underway?
We should, however, not put all of our hopes in this or any one potential vaccine basket. It is crucial to properly assess potential vaccines as they go to human trials and additional animal research may be needed to parallel the human trials to address additional questions.
In this regard, two other coronavirus vaccine studies appear to be the first to have been peer-reviewed and have now been published in the journal Science. These also use monkeys to test other potential vaccine strategies. This development has also been picked up by the media, such as the Boston Globe.
Since these papers are already scientifically peer-reviewed, we will only briefly summarize them.
The first study is by Yu and colleagues from the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center at Harvard Medical School, including other US collaborators and a vaccine manufacturer in the Netherlands (Janssen Vaccines). They tested a vaccine that contained the DNA needed to replicate the SARS-CoV-2 spiny protein. The vaccine was tested in 35 macaque monkeys (25 vaccinated and 10 serving as controls) and showed a substantial reduction in the viral load in the lungs as well as all of the vaccinated animals developing antibodies to the vaccine. The body’s antibodies against the coronavirus are an indication that the virus has been detected and the body can fight it with the antibodies against the virus.
This study required larger numbers of animals probably because vaccines that have DNA coding elements present greater challenges since the DNA may not replicate, or the vaccine just not work as intended. This is yet another strategy for vaccine development and it is currently not clear which strategy may work best.
The second study by Chandrasekar and colleagues is from the same group at Beth Israel Deaconness Medical Center in Boston. They aimed to address whether exposure to the SARS-CoV-2 virus provides protection from re-exposure, a crucial issue for understanding how to manage with global infections.
Nine monkeys were used in this study. The monkeys were exposed to the virus via nasal swabs and developed respiratory symptoms of the disease. After the viral load was cleared they were re-exposed and showed much reduced virus counts and an increased immune cell response, suggesting that the immune response provides protection against reinfection.
Ensuring national capabilities with animal research so that scientists can respond to global need
These studies give hope that a vaccine that works in humans could be available in the near future.
Although it is not clear whether the same effects and benefits would apply in humans, monkeys are the best available model system for testing vaccines for this disease and as seen are already providing data to guide human clinical trials. Also, it is not clear from any of these studies how long immunity would last. How long immunity endures is also a question that can be addressed with longer term studies in monkeys that may well be underway.
These studies are an example of how previous and current research with these precious animals (chimpanzees, monkeys, mice) is. Animal research has been instrumental in developing a relatively rapid scientific response to the current pandemic. This would not have been anywhere near as rapid if the prior animal research during previous epidemics (like SARS and MERS) had not provided a basis.
Also, since nearly all countries have ended laboratory chimpanzee research, the current study was only conducted in mice and monkeys. It is fortuitous that monkeys show similar symptoms as humans, but if they did not and a species more closely evolutionarily related to humans like chimpanzees was needed, those countries might regret their decisions to reduce their capability to conduct research with a small number of chimpanzees that could help millions. A disease may appear in the future that monkeys do not get and without the capability to do research in the appropriate animals, we may well be stuck in a bad position.
Another issue is that the monkey work was conducted in the US, but surprisingly not in the UK, which also has a monkey research programme (the mouse work was conducted in the UK in the first study we considered above). It is not clear why that might be the case, but we wonder whether the regulatory framework or research readiness of the UK or other countries may mean that they are not as ready or quick to respond to national or global need. International collaboration in the first study considered above worked well but that may not always be the case. We encourage all countries to consider their national capabilities with non-human primate science in particular, because further reduction in capabilities would pose a substantial risk to our health in the future.
This point does not only apply to urgent work during pandemics, but also to other important work in the neuroscience of brain function and disorders, which has been criticized and not defended as strongly as it could have been by the NIH. We encourage all institutions conducting animal research to better promote and speak up on behalf of animal research and the regulatory and animal welfare standards that they adhere to and are proud of.
Although animal rights and anti-vaccine groups are taking advantage of the global pandemic, by suggesting that research with animals and vaccines are not necessary and putting their own and other lives at risk, these studies highlight how research with a relatively small number of precious animals can potentially help millions of people take back their lives from this pandemic.
Animal research remains important.
~Prof. Chris Petkov and the Speaking of Research team
Speaking of Research 