Getting Back to Normal: The Need for a SARS-CoV-2 Vaccine

May 18, 2020

Much is riding on the development of a SARS-CoV-2 vaccine. Not only do we want to halt this global catastrophe, but we also yearn for a return to normalcy. We want to throw away our masks, hug our friends and family, visit our loved ones in nursing homes, watch ball games in person, go to the salon, jump in the neighborhood pool. To do those things safely, we need a vaccine against SARS-CoV-2 that offers durable protection, is safe, whose manufacture can be scaled to unimaginable levels and will be globally available to both wealthy and low-income nations.  Fortunately, we have a road map that might lead us there.

As children of the 1950’s, summertime could be a time of fear. If polio showed up in your community, swimming pools were off limits (a difficult sell to 2 avid swimmers growing up a continent apart). Caused by an enterovirus spread by the fecal-oral route, polio was the most feared of all the childhood viruses because of the specter of life-long paralysis—a fate well understood by our fathers, both physicians, who served under history’s most famous polio-induced paralytic, President Franklin D. Roosevelt during World War II. In 1962, we were both summoned to the nurse’s offices at our respective schools where we were given a sugar cube containing a live, attenuated polio vaccine (Sabin vaccine). Both of us had already received injections of inactivated polio virus (Salk vaccine). The Salk vaccine was known to be effective, but experts thought the Sabin vaccine would offer better lifelong protection. Clearly, we were participating in a nation-wide, scientific experiment without the niceties of informed consent or data safety monitoring board oversight. Given summer news reports showing row upon row of iron lungs helping children with paralytic polio breathe, our society trusted scientists and accepted this risk.

Our University of North Carolina (UNC) colleague, Dr. Jim Bryan, recently related his experience as an Epidemic Intelligence Service (EIS) officer at the Centers for Disease Control and Prevention (CDC) at the time of the initial nation-wide distribution of Sabin vaccine. One of Dr. Jim’s first assignments was to investigate an outbreak of paralytic polio in a small, rural South Carolina town at a segregated elementary school. When Dr. Jim arrived at the school, he carried with him the knowledge that the Salk vaccine was widely available, safe and effective, as paralytic polio cases had plummeted nationally from 54,000 to 1,000 cases per year over the previous decade. Dr. Jim quickly learned that this outbreak in S.C. was due to the simple fact that these children were not vaccinated. 

With the widespread use of the Sabin vaccine, Dr. Jim was on a research team that determined that polio cases were occurring in household contacts (primarily adults) of children receiving the Sabin vaccine. The Surgeon General, Dr. Luther Terry, formed an advisory panel which included Sabin and Salk, as well as Dr. Jim, to advise him on the safety of the oral polio vaccine. After intense discussion, the final decision of the panel was the Sabin vaccine was safe. Over the intervening decades, the use of primarily the Sabin polio vaccine led to polio eradication in all of the industrialized world, although pockets of disease exist in regions of Pakistan, Afghanistan and Africa. Ironically, the Salk vaccine is now recommended for use by the CDC in the U.S.

The latter part of the 20th century into this century has seen the development of a remarkable array of new vaccines. Once common childhood viral infections like measles, mumps, rubella and chickenpox are rare due to vaccines. There is hope that cancers associated with hepatitis B and human papillomavirus (HPV) will also be eliminated through aggressive vaccine programs.

In parallel to understanding both the natural history of COVID-19 disease and the correlates of immunity to this virus, research on candidate vaccines has moved forward very quickly. Following the first reported case in December 2019, the viral etiology, the SARS-CoV-2 virus and its genomic sequence were identified in record time. Soon thereafter, the structure of the SARS-CoV-2 spike (S) protein was solved at high resolution, highlighting a potential vaccine target

Research on Other Coronavirus Vaccines

Key findings from prior research on other coronavirus vaccines has contributed to SARS-CoV-2 vaccine design.  Research on the related SARS-CoV and MERS-CoV vaccines demonstrated that the spike (S) protein on the surface is an ideal vaccine target. In SARS-CoV and SARS-CoV-2, this protein mediates fusion with the angiotensin-converting enzyme 2 (ACE2) receptor, and antibodies targeting the S protein have been shown to interfere with this binding and to neutralize the virus. 

Only a small number of SARS-CoV vaccines made it to phase 1 clinical trials before funding was terminated because the virus disappeared from human populations. Vaccines against MERS-CoV, also targeting the S protein, are in pre-clinical and clinical development, including non-replicating viral vector and DNA-based vaccines. 

Key Issues With Vaccine Development

Many issues need to be addressed in the clinical development of vaccines. The goals in early phases of development are to identify a safe, well tolerated and immunogenic dose and dosing regimen. For some vaccine candidates, the use of an adjuvant to boost immune responses may be necessary. Later clinical trials determine the potential duration of protective immunity and potential need for booster immunizations.  Rigorous safety monitoring continues through all phases of testing, as well as after the vaccine comes to market. One long-term safety issue to be explored for this virus is whether vaccinated subjects develop any immunopathologic adverse events when they encounter SARS-CoV-2 infection. Some individuals with severe cases of COVID-19 may develop immunopathologic events, such as a cytokine storm with multiorgan involvement. The medical community needs to monitor for any enhancement of incidence or severity of this type of adverse outcome in those who are vaccinated.  

In addition to meeting clinical development goals, the successful technology transfer to scale-up manufacturing of a vaccine needs to be done which would satisfy the need for global supplies. There is high financial risk to invest time and resources in these activities before substantial safety and immunogenicity are proven. Nonetheless, in this pandemic setting, some large investments are being made within some global public-private partnerships. One example is the work being done within the Coalition for Epidemic Preparedness Innovation (CEPI) group. CEPI is an international non-government organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission and 8 countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway and the UK). Not solely focused on COVID-19, CEPI is also exploring ways to operationalize speedier vaccine development when a pandemic is likely to occur, with a particular focus on 5 viral pathogens (MERS-CoV, Lassa, Nipah, Rift Valley Fever and Chikungunya)  on the priority list at the World Health Organization (WHO), plus Disease X, a human pathogen that has not yet been discovered.

Current Pipeline for SARS-CoV-2 Vaccine Development  

The table below lists SARS-CoV-2 vaccine types in early clinical development. At present, there are 8 investigational vaccines in clinical trials and more than 70 in pre-clinical development. The vaccine platforms are based on modern tools of genetic engineering, as well as known vaccine inactivation technologies.

There is also a program (not listed in the table) repurposing the live, attenuated BCG vaccine used to prevent tuberculosis to determine if non-specific boosting of the immune response might be protective against developing symptomatic disease in healthcare workers at risk for acquiring SARS-CoV-2 infection. Research in mice has demonstrated that BCG-induced immunity is protective against infection with some respiratory viruses including  herpes simplex type 1 and influenza A2 viruses. Two ongoing Phase 3 trials are underway in Australia and the Netherlands enrolling approximately 5,670 subjects in total.
 
SARS-CoV-2 vaccine candidates in clinical trials as of May 18, 2020.
Adapted from the World Health Organization.
Name Vaccine Type Developer(s) Regulatory Status
mRNA-1273 Lipid nanoparticle (LNP)-mRNA Moderna/National Institute of Allergy and Infectious Diseases (NIAID) Phase 2
[Application Approved]
Phase 1
NCT04283461
BNT162 LNP-mRNA BioNTech SE/Pfizer/Fosun Pharma Phase 1/2
NCT04368728
INO-4800 DNA plasmid Inovio Pharmaceuticals Phase 1
NCT04336410
Ad5-nCoV Non-replicating viral vector CanSino Biological Inc./Beijing Institute of Biotechnology Phase 2
ChiCTR2000031781
Phase 1
ChiCTR2000030906
ChAdOx1 Non-replicating viral vector University of Oxford Phase 1/2
NCT04324606
N/A Inactivated virus Wuhan Institute of Biological Products/Sinopharm Phase 1/2
ChiCTR2000031809
N/A Inactivated virus Beijing Institute of Biological Products/Sinopharm Phase 1/2
ChiCTR2000032459
N/A Inactivated virus Sinovac Phase 1/2
NCT04352608

Here is a brief explanation on how the 4 different types of candidate SARS-CoV-2 vaccines work.

Lipid Nanoparticle-mRNA Vaccines

In this vaccine strategy, messenger RNA (mRNA) is packaged into lipid nanoparticles (LNPs), allowing it to enter the cell. The mRNA is then translated into the protein antigen in the cytosol. As with other strategies that rely on intracellular antigen production, these vaccines have the potential to elicit strong T cell response in addition to antibody response. No LNP-mRNA vaccines are currently in use, but they are under development for both cancer and infectious disease targets.

mRNA-1273 is an LNP-mRNA vaccine and was the first SARS-CoV-2 Phase 1 vaccine trial to be initiated. Moderna and the NIH Vaccine Research Center are co-developing the vaccine, which encodes for full-length, pre-fusion stabilized spike (S) protein from SARS-CoV-2. The U.S. Food and Drug Administration recently approved an mRNA-1273 Phase 2 trial.
 
Likewise, BNT162, being developed by Fosun Pharma, Pfizer and BioNTech, is a LNP-mRNA vaccine. They are testing 4 chemically-modified variations of mRNA, all encoding the S protein, in combined Phase 1/2 trials in Germany and the U.S.

DNA Plasmid Vaccines

Graphic representation of a SARS-CoV-2 viral particle and the 4 types of vaccine candidates currently in clinical trials.
Graphic representation of a SARS-CoV-2 viral particle and the 4 types of vaccine candidates currently in clinical trials.
Source: American Society for Microbiology
DNA plasmid vaccines encode antigen genes on a small circular piece of DNA. The plasmid is injected into the appropriate tissue, where cells then take it up. To enhance uptake efficiency and specificity, some companies have developed proprietary delivery technology.
 

Inovio Pharmaceuticals developed a DNA plasmid vaccine candidate modeled from the virus' S protein sequence. The plasmid is delivered into cells by a proprietary injection and electroporation system. One Phase 1 trial is being conducted in the U.S., and a second trial is underway in South Korea. 

Non-replicating Viral Vector Vaccines

The idea of using viruses to ferry genes into human cells may be more familiar in the context of gene therapy, but vaccinologists have latched onto a similar idea - viral vector vaccines use the shell of a virus capable of infecting human cells to deliver 1 or more antigen genes from a different pathogen (or even pathogens). The natural ability of the virus to infect human cells is left intact, but the infected cells produce the antigen protein(s) instead of viral proteins. Some viral vaccine vectors are further engineered to be non-replicating, offering the additional protection of being unable to copy themselves inside infected cells. There are many veterinary viral vector vaccines in use that have shown the strategy to be both safe and effective.

CanSino Biologics has developed a recombinant novel coronavirus vaccine, Ad5-nCoV, that incorporates the S gene of SARS-CoV-2 into the adenovirus type 5 vector (Ad5). The vector is capable of delivering the S gene directly to the nuclei of many types of human cells, where the gene is then translated into the S protein antigen. In addition, studies show that the Ad5 vector triggers strong antibody and T cell responses to its transgenic antigens. Ad5-nCoV’s Phase I trial began in March, and Phase 2 is recruiting.

The Oxford Vaccine Group at the University of Oxford has identified a new vaccine candidate for COVID-19, a chimpanzee adenovirus vaccine vector called ChAdOx1. Pre-existing vector immunity within the human population is an issue for vectors derived from human viruses, but using a virus from another species circumvents this potential complication. The Oxford team has previously developed a MERS vaccine. Initiation of their Phase 1/2 combined trial is imminent.

Formalin-inactivated and Alum-adjuvanted COVID-19 Vaccines     

Inactivated vaccines consist of heat-, radiation- or chemically-killed pathogens. The Salk polio vaccine is a chemically-inactivated vaccine, and many inactivated vaccines for human diseases have been in use for decades. These vaccines typically elicit a weaker immune response than live-attenuated vaccines and may depend on an adjuvant to encourage a more robust immune response.

Sinovac is developing a formalin-inactivated and alum-adjuvanted candidate vaccine that was shown to protect rhesus macaques from SARS-CoV-2 infection. Their combined Phase 1/2 trial is ongoing. Similarly, the Beijing Institute of Biological Products and Wuhan Institute of Biological Products are co-developing an inactivated vaccine, which is in combined Phase 1/2 trial.

It could take between 12-18 months to develop a vaccine ready for market, assuming the process from vaccine candidate preclinical selection, proof-of-concept in clinical trials, manufacturing scale-up and market availability goes smoothly. SARS-CoV-2 vaccines presently under clinical development might be licensed and available too late to impact the first wave of this pandemic. However, they may be useful in reducing morbidity and mortality if additional waves occur, or in a post-pandemic scenario with SARS-CoV-2 circulating seasonally. 

As we look forward to the development of the SARS-CoV-2 vaccine, the following questions need to be answered.
  1. Will the vaccine elicit a protective immune response?
  2. How safe will the vaccine be? 
  3. How much will the vaccine cost and how will that cost be borne?
  4. How will vaccine distribution be prioritized to assure the most vulnerable and their care providers receive it first?
  5. If there are multiple, competing effective vaccines, as there were for polio, how will we determine which one to give priority? Who will make these decisions?
Finally, as we prepare for a potential second wave of COVID-19 this fall, it is incumbent upon everyone to get a flu shot. Each year, only half of U.S. adults get a flu shot. The flu shot is not perfect, but by getting it, you lessen your risk of hospitalization, making more resources available to combat the next COVID-19 wave. If you want to both help yourself and our heroic health care professionals, get your flu shot!
 

Author: Lynn Smiley, M.D.

Lynn Smiley, M.D.
M. Lynn Smiley, M.D. is an infectious disease physician with extensive clinical development experience with viral diseases. 

Author: Peter Gilligan, Ph.D., D(ABMM), F(AAM)

Peter Gilligan, Ph.D., D(ABMM), F(AAM)
Peter Gilligan is the former Director of the Clinical Microbiology-Immunology Laboratories of the University of North Carolina Hospitals.