Recent outbreaks: a focus on COVID-19 and Ebola
by Martina de Majo, PhD | June 9, 2020
Viruses are minuscule biological entities composed of proteins and genetic materials (DNA or RNA) that cannot be observed by the naked eye. They are microorganisms that need to infect a host’s cells to produce many copies of themselves, which will subsequently infect other neighboring cells. Over time, society has learned to fight some of these pathogens through the development of therapies and preventive measures of which vaccines are significant players. Conventional vaccines are composed of weakened or killed versions of a pathogen that, once delivered, will train the body’s immune system to recognize that pathogen and organize a targeted immune response that will efficiently get rid of the infectious agent, should it encounter it again.
How are vaccines developed?
Vaccine development usually takes between 10-15 years. The process is divided into three general steps: 1) laboratory and animal studies, 2) clinical studies with human subjects, and 3) approval and licensure.
The first step consists of finding a portion of the pathogen that can be used to stimulate the production of antibodies. Once a candidate is found, its safety and efficacy are verified in in vivo and in vitro pre-clinical models. In the US for instance, if the candidate proves effective through pre-clinical studies, an investigational new drug (IND) application is then submitted to the US Food and Drug Administration (FDA), which has 30 days to review it. Once approved, this marks the end of the preclinical stage and the beginning of the clinical studies.
In the clinical studies, vaccine candidates are tested on a small cohort to verify their safety (phase I). If results suggest that it is risk-free, the vaccine is approved for phase II. In phase II, the vaccine is tested on a larger group of individuals to evaluate its efficacy, safety, dose, and method of delivery. If successful, the vaccine will be tested on a much larger cohort to verify unpredictable side effects along with its efficacy on a wider scale (phase III). Once the vaccine passes these tests, it is ready to be submitted for a biologic license application to the FDA.
Next, the vaccine is released for administration to the public and will undergo monitoring by both the manufacturer and the FDA through the vaccine adverse event reporting system (VAERS), a voluntary reporting system available to individuals treated with the corresponding vaccine. Newly developed vaccines are also monitored by the center for disease control and prevention (CDC) through a database called vaccine safety datalink (VSD) and can undergo an optional phase IV where adverse effects are monitored at the population level. This process is very similar to the drug approval process, if not even more strictly regulated, as the assumption is that a vaccine will reach more individuals that any other treatment.
Until the 1900s, infectious diseases were responsible for the highest number of deaths worldwide. Over the last century this percentage drastically decreased, due to advances in science and technology, and better public health measures. Among these, a major role was played by the development of vaccines that eradicated several deadly pathogens such as smallpox and poliomyelitis. Other pathogens, however, still pose a threat, causing epidemics and sometimes even pandemics (epidemics that spread over countries or continents). These infectious agents include human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), numerous flu viruses, Ebola virus (EBOV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory syndrome coronavirus (MERS-CoV), and the most recent SARS-CoV-2, which causes the coronavirus disease 2019 (COVID-19). Most of these viruses originate in wildlife reservoir and then spill over to humans either directly or via intermediate hosts. For instance, both SARS-CoV and SARS-CoV-2 were found to have spilled over from bats to humans, SARS-CoV-2 probably using the pangolin as an intermediate host. The world has responded in similar ways to these epidemics, mainly by identifying the virus, reducing its spreading with public health orders as well as investing in research to find therapies and ideally vaccines. However, it is common during epidemics to face several critical challenges, such as difficulty in diagnosing the infecting agent, sudden overloading of healthcare systems, and consequent struggle in caring for the infected individuals.
COVID-19 and Ebola
COVID-19 is a pathology affecting the respiratory tract, which is caused by a novel virus belonging to the family of the coronaviruses: SARS-CoV-2. This virus is extremely contagious and has been able to spread globally in a short amount of time. The relentless, rapid and global spread of SARS-CoV-2 led the world health organization (WHO) to classify it as a pandemic on March 11th, 2020. As of June 2nd 2020, this virus has infected 7,193,476 and killed 408,614 people worldwide.
Although not as infectious as SARS-CoV-2, EBOV is a highly lethal virus that causes hemorrhagic fever with an average mortality rate of 50% (ranging between 25% and 90% in different outbreaks). Transmission of EBOV happens through direct contact with body fluids of symptomatic patients. The first Ebola outbreak was registered in Sudan and Zaire (now Democratic Republic of Congo, DRC) in 1976. Since then, there have been numerous outbreaks with the most extensive being between 2013 and 2016 in West Africa, which had 28,646 suspected cases and around 11,000 deaths, 10% of which were healthcare workers. Nosocomial (hospital-acquired) transmission has been one of the major causes of morbidity and mortality in the Ebola outbreaks, especially in cases where the disease was misdiagnosed or unknown. This is very apparent in the COVID-19 pandemic, as healthcare professionals face the biggest threat because of scarcity of adequate personal protective equipment (PPE), and insufficient knowledge of the infectiousness and range of symptoms of SARS-CoV-2.
Mirella Biava was one of the biologists working at Lazzaro Spallanzani National Institute for Infectious Disease in Rome, Italy at the time of the 2013-2016 Ebola outbreak in West Africa. Mirella was recruited by the Italian foreign affairs ministry to help with testing and setting up a diagnostic center to control the spread of the virus in Sierra Leone. She described that, during this time, the country enforced lock-down and finely regulated procedures to test suspected positive samples and limit transmission. After the initial mission, Mirella went back to Sierra Leone five times and witnessed a gradual loosening of the strict measures when the infection was under control with most of the cases hospitalized or isolated. The resolution of the Ebola crisis in Sierra Leone was reached due to an intense effort by the local health system and government institutions, non-government organizations (NGOs), such as the Italian Emergency, and medical and scientific aid from more developed countries.
The (re)discovery of an Ebola vaccine
As Mirella explains to BCBA, the major and most effective weapon to defeat an infectious disease is finding a vaccine. As for Ebola, one of the most promising vaccines, known as Ervebo, was developed in the early 2000s by a laboratory part of the Canadian Science Centre for Human and Animal Health (CSCHAH) in Winnipeg, Manitoba (Canada) and led by Heinz Feldmann. It was found to be safe and effective by 2005, but received very little interest, being eventually bought by the Iowa-based BioProtection Systems Corp, that discontinued it. Mainly because of scarcity of funding, perhaps due to Ebola primarily affecting third-world countries, the Canadian lab that originally developed the vaccine halted research on Ebola. However, in 2010 Judie Alimonti, who was working in the same laboratory but under the guidance of a new group leader, Gary Kobinger, initiated the development of the human-grade EBOV vaccine for testing.
Fast forward to 2014, the Ebola outbreak in West Africa was rapidly evolving. Suddenly there was a growing interest in finding a therapy and the Canadian lab led by Kobinger contacted the WHO to share their findings. The WHO, however, deemed unethical to administer drugs at the preclinical stage to the population of West Africa. Nevertheless, a few months later, when the Ebola outbreak was declared a global health emergency, the Canadian government and other institutions donated the vaccines they developed to the WHO. BioProtection Systems Corp that initially bought the Canadian vaccine to enlarge their portfolio and to attract investors was not interested in clinically testing it, so another pharmaceutical company, Merck, stepped up.
After long negotiations, Merck bought the vaccine in November 2014 for $50 million and, in collaboration with the WHO, the US national institute of health (NIH) and CDC tested the vaccine in Liberia and Sierra Leone by ring vaccination, a method that only allows the vaccinations of the people in contact with the infected individuals. The trial was later extended to Guinea as a result of the WHO’s and the French division of doctors without borders’ (MSF) efforts. While trials were concluded in less than a year with very encouraging results, there was some criticism by experts for not following rigorous testing criteria, which was formalized in 2017 in a report released by the National Academy of Sciences. Nonetheless, the vaccine was proven successful and approved in November 2019, almost 20 years after its discovery.
Lessons learned from the Ebola Crisis
Jerome Bouquet, PhD, is a scientist at AstraZeneca working on viral surveillance and SARS-CoV-drug development. He explained to BCBA that one valuable milestone reached during the Ebola epidemic was the ability to track different Ebola strains in real time using next generation sequencing (NGS). NGS allowed the use of molecular epidemiology to follow reservoir and human to human transmission and provide information on the source of contagion. This, coupled with the advance in technology which brought NGS to mobile labs in West Africa, was a huge step towards understanding the applicability of newly developed therapeutic strategies and vaccines to upcoming outbreaks. In fact, NGS allowed scientists to understand in real time that Ervebo could be effective in the outbreak taking place in the Equateur Province of the DRC in 2017. The vaccine was therefore distributed in the area and perhaps helped to end the outbreak 42 days later. By sequencing the EBOV strain emerging from another outbreak in a different region of the DRC, scientists were also able to understand that the outbreak was caused by a strain that was unrelated to the one in the Equateur Province. Plainly, the ability to sequence a virus’s full genome in real time has practical consequences in public health measures and in choosing effective therapies.
Real time NGS also helps uncover the mutation rate of viruses. RNA viruses (like EBOV and SARS-CoV-2) tend to mutate quickly. However, as Jerome explains, both EBOV and SARS-CoV-2 rapid spread resulted in few mutations so far, increasing the likelihood of therapies to be effective on more strains. Even so, there are areas of the viral genome that tend to mutate more frequently. Jerome explained that a specific surface protein (protein S) is often considered for vaccine development. This is relevant to SARS-CoV-2 vaccine development as this novel virus also exhibits an S protein. Interestingly, there is one region of SARS-CoV-2 S protein that is particularly mutation prone, therefore, when developing a vaccine, caution is warranted on what fragment of this protein is considered.
Overall, many lessons can be learnt from the Ebola outbreaks. The vaccine Ervebo was developed almost a decade before the outbreak and had the potential to save thousands of lives. However, it was not clinically tested since Ebola was not considered an imminent threat and it was only fully approved when the epidemic was already over, requiring a considerable amount of money and urgent effort. Ultimately, Ervebo’s story stresses the importance of a global collaboration of the public and private sector for a timely and successful vaccine development. One of the reasons why it was possible to obtain testing for SARS-CoV-2 quickly was due to its homology with SARS-CoV. Similarly, the reasons behind the optimistic predictions of obtaining a vaccine against SARS-CoV-2 within 12-18 months are also due to the ability of repurposing part of the vaccine already developed for SARS. Therefore, it is important to invest and support research in a variety of infectious disease in a preventive manner, in order to be better prepared for future health crisis.
Martina de Majo is a postdoctoral scholar at the department of Ophthalmology, School of Medicine, UCSF