Human coronaviruses (HCoVs) in the past were considered to cause nothing more than the common cold in healthy people. That changed with the advent of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) in the past decade. The latest coronavirus─2019-nCoV, since renamed by the World Health Organization as COVID-19─emerged in December 2019 in Wuhan, China. As of late February 2020, it had sickened tens of thousands and killed nearly 3000 people.

Four of these large, enveloped, positive-strand RNA viruses are endemic globally and thought to cause 10–30% of upper respiratory tract infections in adults (1). They possess a surface spike (S) glycoprotein that binds to host cell receptors, and the nature of this protein is believed to determine the main properties of each coronavirus. SARS-CoV was the first coronavirus to jump from animals to humans; MERS-CoV and COVID-19 have as well.

The genetic sequence for COVID-19 was released to public databases on Jan. 10, 2020 by the Shanghai Public Health Clinical Center & School of Public Health (1). The three-dimensional (3-D) structure of the spike protein suggests that it binds more tightly to human cell surface receptors than SARS-CoV, a possible reason that this coronavirus exhibits greater infectivity (2).

Platform diagnostic methods have been rapidly adapted to include COVID-19 for early identification of cases. Several academic and industrial researchers have also focused on applying novel vaccine development and manufacturing platforms to the accelerated development of a COVID-19 vaccine.

In terms of vaccine development and protection against dangerous viral pathogens, there is nothing particularly unique about coronaviruses, according to Eric von Hofe, chief scientific officer of NuGenerex Immuno-Oncology. “All of the recent potentially pandemic viruses, including SARS and MERS and two flu viruses (avian and swine flu), have the common feature that they simply had never been seen before by the human immune system. That said, we now know a lot about how the human immune system protects against viral infections and can rapidly identify the critical parts of a new virus to target for vaccine development,” he says.

Platform technologies are ideal

Traditional vaccines, like the seasonal flu vaccine, are made by growing up large quantities of the virus and in some way killing or inactivating it so that it can be used safely as a vaccine. This approach is an old technology from the middle of the past century, according to von Hofe. “The main problem here is the time it takes to produce the vaccine, which is at least a year and can be several. Ideally, we’d have a platform technology that could be used to produce a vaccine in a few months,” he observes.

Such technology platforms should be flexible enough to respond to any new viral threat. “We would like to have a simple ‘plug-and-play’ setup where the critical components of a new virus required to make the vaccine can be determined by rapid computer analysis and plugged into the platform to generate a vaccine,” von Hofe notes. “Getting all of the critical components produced and structured in a way that perfectly models the vaccine is the big challenge,” he adds.

A reductionist approach is best

The best way, von Hofe says, is to follow a reductionist strategy to identify key viral components that alone produce complete protection in a safe vaccine that can be manufactured rapidly and in a cost-effective manner. “Clearly this is a tall order, but we’re making good progress in that direction,” he asserts.

As an example, he points to the development of subunit vaccines that rely on recombinant DNA to encode a critical subunit of the vaccine that generates a response. There are additional challenges to this approach, however. “While responses can be produced, the protection may be short-lived, as there is no guarantee that immunological memory will be generated as is possible with a whole virus vaccine,” von Hofe comments.

The DNA approach against COVID-19

San Diego-based Inovio Pharmaceuticals is one company developing a DNA-based vaccine against COVID-19. The biotech was the first to advance a vaccine (INO-4700) against MERS-CoV into human testing and is currently preparing to initiate a Phase II trial for INO-4700 in the Middle East. This vaccine, however, cannot be used against COVID-19 because the two coronaviruses are too different.

To develop a new vaccine, Inovio first converts the virus’ RNA into DNA and identifies short sections that will, according to computer simulations, generate the greatest immune response. The plasmids are then produced in large quantities using bacteria. The overall development and approval timeline is thereby significantly reduced.

Inovio began animal testing of INO-4800, its COVID-19 vaccine candidate, in February 2020 and is aiming to begin human safety testing in early summer 2020. The company will conduct tests in both the United States and China, the latter in collaboration with Beijing Advaccine Biotechnology Co. (3). Work in the US is supported by a $9-million grant from the Coalition for Epidemic Preparedness Innovations (CEPI). The collaboration with Beijing Advaccine is anticipated to accelerate developed on INO-4800 in China by providing access to not only its vaccine expertise, but also its relationship and experience with Chinese regulatory authorities and clinical trial management in the country.

Prophylactic Messenger RNA Vaccines

Two companies, both also supported by grants from CEPI, have developed platform technologies based on messenger RNA (mRNA). Cambridge, MA-based Moderna—which has developed numerous prophylactic mRNA vaccines with positive Phase I clinical readouts and also has a fully integrated clinical-material manufacturing site—is progressing its COVID-19 vaccine candidate (mRNA-1273) into the clinic (4,5). The Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), collaborated with Moderna to design the vaccine. NIAID will conduct investigational new drug-enabling studies and a Phase I clinical study in the US.

Moderna’s mRNA vaccines can contain multiple mRNAs coding for different proteins and mimic natural infection, thus stimulating a more potent response, according to the company. Only the coding region of the mRNA must be changed for each new vaccine. The rapid discovery approach and the manufacturing agility of mRNA vaccine design and production also make it an effective platform technology.

Just 42 days after sequence selection, Moderna shipped the first batch of mRNA-1273 to NIAID for use in a planned Phase I clinical study in the US. The mRNA vaccine encodes for a prefusion stabilized form of the COVID-19 S protein.

German biotech CureVac also has an mRNA platform technology for vaccine development and manufacturing suited for rapid response to viral outbreaks, it says (6). Using an extensive in-house nucleotide sequence library, CureVac is able to identify optimum sequences for any given vaccine target and eliminate the need for chemical modification, shrinking the development timeline.

The company has also developed specific carrier molecules for its mRNA products, including lipid nanoparticles (LNPs), developed in partnership with Acuitas Therapeutics and Arcturus Therapeutics). It is developing The RNA Printer, a mobile, automated production unit for rapid supply of LNP-formulated mRNA vaccine candidates.

Stabilizing the pre-fusion virus form

A fourth group receiving funding from CEPI for application of a vaccine platform technology to accelerated development and manufacture of a COVID-19 vaccine is located at Australia’s University of Queensland (UQ) School of Chemistry and Molecular Biosciences (7). Its rapid response technology relies on molecular clamp technology, an approach developed by UQ researchers and patented by UniQuest.

The molecular clamp technology is used to create subunit vaccines against class I and III enveloped viruses by stabilizing the pre-fusion form of viral fusion proteins, thus mimicking the protein conformation found on live virus and generating a strong immune response. A polypeptide is used to maintain the pre-fusion structure and prevent the protein from folding after entry into the cell.

The platform technology, which does not require prior knowledge of a protein’s quaternary structure, therefore facilitates the expression of recombinant viral glycoproteins without loss of native antigenicity (8). It has previously been used to produce chimeric polypeptides that mimic the pre-fusion conformations of several enveloped viruses. The goal is to complete preclinical development within 16 weeks and then progress directly to Phase I clinical trials, with completion of that step in 10 weeks, followed by large-scale production of more than 200,000 doses in eight weeks.

For its COVID-19 vaccine, the UQ researchers created a first candidate in the laboratory in just three weeks (9). This work confirmed that the engineered vaccine candidate is readily recognized by the immune system and triggers a protective immune response. Plans for preclinical testing were underway as of late February, and the researchers hope to begin clinical testing by mid-2020.

Leveraging computer technology

NuGenerex Immuno-Oncology is focusing on what von Hofe refers to as the smallest and simplest fragments of the virus needed to produce an immune response. These short fragments of proteins are identified by a computer algorithm and can be made rapidly by entirely synthetic means. They are modified to ensure that they activate immune cells that are key in producing immunological memory. “While these virus fragments may not produce as complete a response as whole inactivated viruses, they basically produce a ‘memory’, so when a person treated with our vaccine does encounter the virus, he or she is more prepared to mount an effective response,” von Hofe explains. The technology is also a platform approach because it can be applied to virtually any virus that may emerge as a threat.

Big Pharma has programs too

While these smaller biotechs have generated attention for their accelerated development platforms, Big Pharma companies have also been actively working on COVID-19 vaccine candidates. Both Johnson & Johnson and Sanofi are collaborating with the US Department of Health & Human Services (HHS).

Johnson & Johnson’s Janssen Pharmaceutical Companies unit is collaborating with the HHS’ Biomedical Advanced Research and Development Authority (BARDA) to rapidly advance the initial stages of Janssen’s COVID-19 vaccine development program, which is based on its AdVac and PER.C6 platform technologies (10). BARDA is funding accelerated development of a candidate into Phase I clinical trials, while Janssen is upscaling its manufacturing capacities.

Sanofi Pasteur, the vaccines global business unit of Sanofi, is also collaborating with BARDA, using its established recombinant DNA technology platform to accelerate the development of a potential COVID-19 vaccine (11). This technology produces an exact genetic match to proteins found on the surface of the virus, which are then expressed using Sanofi’s insect (baculovirus) expression platform. The technology is used for Sanofi’s licensed recombinant influenza vaccine and a SARS vaccine that has been shown in non-clinical studies to be immunogenic and afford partial protection in animal challenge models.