In the Shadow of COVID-19, Will Other Vaccine Development Programs Be Left Behind?

by Hillary Johnson, MHS

ON FEB. 27, 2020, members of the White House Coronavirus Task Force held a press conference in the White House Press Briefing Room.¹ On that date, there were 15 confirmed cases of coronavirus disease 2019 (COVID-19) in the United States, all the result of recent travel, and there was not yet evidence of sustained community transmission. Yet, a question on everyone’s mind was the status of a novel coronavirus vaccine. President Trump prefaced by stating the U.S. was rapidly developing a vaccine, and it was coming along well. Secretary of Health and Human Services Alex Azar listed vaccine and therapeutics development among the White House’s top-five priorities in their request for funding from Congress. But, it was Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, who spoke to the realities of developing a global vaccine.

Phase I and II clinical trials (determining safety and immunogenicity) would take about six months, he estimated. Then, he said, the vaccine would graduate “to a trial that involves hundreds if not low thousands of people to determine efficacy. At the earliest, an efficacy trial would take an additional six to eight months. So, although this is the fastest we have ever gone from a sequence of a virus to a trial, it still would not be any applicable to the epidemic unless we really wait about a year to a year and a half.”

For the emerging global pandemic, it was clear, a vaccine would not be the answer over the next year. Dr. Fauci continued, “However, if this virus — which we have every reason to believe it is quite conceivable that it will happen — will go beyond just a season and come back and recycle next year — if that’s the case, we hope to have a vaccine.”

And with that, COIVD-19 joined the long list of global infectious diseases with ambitious targets for mitigation through vaccination. But as a world in quarantine shifts focus and resources to COVID-19 response, where are we with other emerging infectious diseases that very recently also dominated the global newsreel, namely the Zika and Ebola viruses?

The Zika Virus

In March, the International Olympic Committee postponed the 2020 Tokyo Olympic Games due to the spread of COVID-19. While this will be the first time in Olympic history that the Games are postponed,² it is not the first time concerns over a spreading virus have cast a shadow over the global event. The previous Summer Games in Rio de Janeiro sparked a heated debate over safety and the possibility of Zika virus transmission, as outbreaks in Brazil beginning the year before resulted in an estimated 200,000 cases.³

Spread mostly by the bite of an infected Aedes species mosquito, Zika virus typically causes mild clinical symptoms, and many infected have no symptoms at all. However, in 2016, the World Health Organization (WHO) declared a Public Health Emergency of International Concern⁴ based upon accumulating data showing the link between Zika virus in pregnancy and fetal birth defects, as well as the potential for Guillain-Barré syndrome in infected adults.

Multiple scientists and organizations called for the Games to be canceled, but WHO ultimately determined there was no public health justification for postponing or canceling the games⁵ based upon an assessment at the time that Zika virus was already circulating in almost 60 countries globally and 39 countries in the Americas. However, WHO did advise pregnant women not to travel to Rio de Janeiro.

The Summer Olympics came and went with minimal Zika fanfare (WHO reported no new cases associated with the event⁶), but the threat of Zika virus did not immediately abate. That year, the U.S. reported more than 5,000 cases within the United States and more than 36,000 cases in the U.S. territories.⁷ A 2016 Lancet study⁸ estimated more than two billion people were potentially at risk for Zika virus infection across Asia and Africa. With data on the association between Zika virus and microcephaly in infants continuing to mount, interest in development of an acceptable vaccine candidate was also growing. WHO announced a Zika virus vaccine target product profile (TPP) for emergency use that same year.⁹

TPPs describe the desired characteristics of a product that will address a certain disease, and the TPP for Zika virus vaccine was no small feat. This “wish list” for a Zika vaccine included preventing clinical illness in subjects 9 years and older, and providing at least a year of protection in a single dose, a long shelf life when frozen and acceptable use in pregnant and lactating women.

As with many vaccines proposed for the global stage, logistics can be a primary barrier. Complex cold chain storage requirements make many vaccines suboptimal in warmer climates with questionable power consistency. The ideal Zika vaccine will need to be easily stored and administered, particularly in warm rural climates.

But beyond common logistical concerns, a potential vaccine faces significant challenges. Early research stumbled due to initial deficiencies in animal modeling (many preliminary efforts to generate different Zika virus strains in mice were unsuccessful).¹⁰ Additionally, Zika virus sequelae of greatest concern pertain to pregnant women, a challenging priority population for vaccine development; it is not yet known if correlates of immunity for fetal protection differ from those that will be identified for prevention of disease in the mother.¹¹ Also at issue is live vaccines are contraindicated in pregnancy, potentially limiting vaccine design options.

Zika virus is a flavivirus and shares a similar genome to other Flaviviridae RNA viruses known for causing widespread morbidity and mortality around the world (examples include Japanese encephalitis, yellow fever and West Nile).¹² But it is its resemblance to the dengue flavivirus that is most notable and creates multiple challenges in geographic areas where both viruses can be found. To begin, many diagnostic tests have difficulty distinguishing between dengue virus and Zika virus due to cross-reacting antibodies. At the patient level, this can make an explicit diagnosis challenging. But in a clinical trial, where researchers would be looking to measure baseline antibodies pre- and post-infection, as well as pre- and post-vaccination, the ability to distinguish between Zika virus and pre-existing immunity to dengue virus in a population is paramount.

Then, there is the theoretical phenomenon of antibody-dependent enhancement (ADE), a suboptimal antibody response to the dengue virus, and due to their flavivirus similarities, it is not yet known if the same phenomenon could apply to Zika as well.¹¹ With ADE, infection with one dengue serotype may produce mild illness and leave behind heterotypic antibodies. But if a patient is reinfected at a later date with a different serotype, their leftover cross-reactive but non-neutralizing antibodies can actually help the invading virus by binding with it but not neutralizing it. The theory behind ADE is that the binding antibodies from the previous infection serve as a Trojan horse for the virus entering a cell, allowing significant viral replication and, ultimately, much more severe disease.

Due to the similarities across flaviviruses, the question remains: Is the body’s immune response to Zika affected by natural immunity to other flaviviruses and potentially by other flavivirus vaccines?

Yet, progress has been made. The Mayo Clinic published a state of the science review of Zika vaccine development in late 201913 in which it mentioned more than 30 Zika vaccines in various stages of development, from early stage research to Phase II clinical trials. The proposed formulations run the gamut: live virus, inactivated virus, whole-virus, subunit, mRNA, protein and vector-based formulations. But the most advanced vaccine candidates reported in the paper are two DNA-based plasmid vaccines (encoding for prM and E proteins of a French Polynesian strain of Zika) showing success in mouse and rhesus macaques animal studies and now undergoing Phase II clinical trials in healthy adults. The Mayo Clinic additionally highlights a purified, inactivated, whole-virus, alum-adsorbed vaccine developed using the same platform as the IXIARO Japanese encephalitis vaccine in which early studies show success in eliciting neutralizing antibodies. All promising, considering this emerging pathogen only really came to the global forefront in 2016.

Unfortunately, global attention has waned due to epidemiological uncertainties. Incidence of Zika virus infection peaked in the Americas in 2016, but substantially declined in 2017 and 2018. In 2019, there were no confirmed cases of Zika virus in the U.S. territories.⁷ On the surface, decreases in incidence are desired. Yet not knowing when and where the next outbreaks will occur makes clinical trial site selection difficult, and progression to more Phase II and Phase III clinical trials may be problematic. Single injections of supplemental funding in outbreaks can jump-start progress (as in 2016), but if not sustained, progress can stymie. For Zika virus vaccines, the next stage for vaccine development may be a long time in coming.

The Ebola Virus

The quest for Ebola vaccine development may share some similarities with Zika (both emerging pathogens of global concern); however, one key difference is clear. The Ebola vaccine candidates benefited from already being in development when relevant outbreaks struck.

The 2014-2016 Ebola outbreak in Western Africa dominated international headlines. Travelers leaving West Africa were screened at airports, and the United States even implemented enhanced entry screening by diverting travelers to designated airports and requiring traveler health monitoring for a period of time following entry to the U.S.¹⁴ (similar to international travel restrictions for COVID-19 in early 2020). WHO declared the outbreak a Public Health Emergency of International Concern, and over the two-and-a-half-year epidemic, the world would see more than 28,600 cases and 11,325 deaths across 10 different countries,¹⁵ in what would become the largest Ebola outbreak in history.

Ebola virus disease (EVD) is a rare but deadly disease first discovered near the Ebola River of the Democratic Republic of Congo (DRC) in the 1970s. Spread through direct contact with the bodily fluids of an infected person, EVD can cause hemorrhagic fevers, diarrhea, vomiting and, in up to half of cases, death.¹⁶ Healthcare workers are particularly at risk; a WHO study from the West Africa Ebola outbreak found health workers were between 21 and 32 times more likely to be infected with Ebola than the general population, and two-thirds of those infected died.¹⁷

Multiple response activities are credited with ending the Western Africa outbreak, including strong government partnerships, establishing laboratories and improved surveillance methods, community mobilization and hygiene education campaigns, and building local trust. The well-timed introduction of a powerful vaccine and implementation of a ring vaccination strategy also made it possible to limit the spread of the epidemic. The prodigal vaccine, Ervebo, is manufactured by Merck, and consists of a recombinant vesicular stomatitis virus as a vector that is genetically engineered to contain a glycoprotein from the Zaire strain of the Ebola virus. Phase I and II trials were well underway (confirming safety and immunogenicity), allowing Phase III trials (looking at efficacy) and the tail end of the outbreak to align in 2015.

In a trial, following laboratory confirmation of a case, researchers identified contacts and contacts of contacts for targeted vaccination efforts, known as a ring vaccination strategy and modeled after smallpox vaccination efforts. Through ring vaccination, everyone who has been, or could have been exposed to a diseased patient receives the vaccine. The trial was a success, showing a vaccine efficacy of 100 percent.¹⁸ The same strategy was applied again in 2018 when DRC began its current Ebola outbreak. Preliminary study data from DRC show a 97.5 percent efficacy rate, and also suggest that vaccinating people after infection can reduce their chance of dying.¹⁹

Through compassionate-use protocols and the clinical trials in the DRC, more than 290,000 people20 have been vaccinated so far with Ervebo. DRC, Burundi, Ghana and Zambia all announced they were licensing Ervebo in February, meaning they will be able to stockpile and administer the vaccine going forward outside of clinical trials.

In September 2019, Congolese health authorities began administering a second Ebola vaccine under a compassionate-use protocol. This second Ebola vaccine employs a different strategy to expand protection, bypassing the identified close contacts and social networks of ring vaccination targeted with Ervebo, and instead is being administered in the surrounding geographic areas without confirmed Ebola transmission, but still potentially at risk. The two-dose regimen leverages two different vaccines (Ad26.ZEBOV and MVA-BN-Filo) administered eight weeks apart. The vaccines utilize a viral vector strategy (genetically modifying adenovirus serotype 26 [Ad26] and modified vaccinia virus Ankara [MVA]) to safely induce the production of Ebola virus proteins and trigger an immune response. Together they are referred to as the Janssen vaccine regimen and are manufactured by Johnson & Johnson.²¹

Looking Forward

When compared with Zika, Ebola virus prevention programs seem better situated for potential challenges ahead due to the new availability of an internationally licensed vaccine (and additional vaccines in the Phase III pipeline). But a drain on international resources caused by novel coronavirus could threaten the upkeep of surveillance and response operations for both diseases worldwide. The Ebola outbreak in DRC was just two days shy of reaching the milestone of two incubation periods (42 days) with no new cases when an additional case was identified in the town of Beni in April. Reaching that milestone would have declared an end to the world’s second largest Ebola outbreak. Instead, confirmed cases rose to 3,476 (with 2,276 deaths), and the clock reset for tracking another two incubation periods.22

Both the Zika virus and the Ebola virus have had their moments as emerging pathogens of global concern. But sustained progress in prevention will require a continued seat at the international table. Under current circumstances, maintaining a high global profile in the era of the COVID-19 pandemic (essential to ensuring continued resource allocation and capacity development) will be difficult.

HILLARY JOHNSON, MHS, has a graduate degree in health sciences from the Johns Hopkins Bloomberg School of Public Health and has worked in STD and HIV prevention both domestically and in Africa. She is currently an epidemiologist with the Massachusetts Department of Public Health’s Immunization Program.