It is hard to believe that within one year of the declaration of the pandemic, as many as eleven COVID-19 vaccines received emergency authorized use. Despite producing enough of these vaccines to administer 6.7 billion doses by the end of September 2021, more than 65 percent of the world’s population remains unvaccinated. A variety of challenges have significantly compromised the ability to distribute the vaccine to remote or underserved areas, such as cold-chain transportation and storage requirements, the need for medically trained professionals to administer vaccinations, and managing multiple doses spaced weeks apart.
Just as innovation fueled the rapid development of the first wave of COVID-19 vaccines, innovation will also provide solutions to overcome these challenges. The following candidates currently in clinical trials demonstrate the variety of different approaches to solving the problem and may help to meet the ongoing global need:
Vaxart – Protection in a Pill
The fact that Vaxart’s COVID-19 vaccine (VXA-CoV2-1) is delivered via a pill is a clear innovation, eliminating many of the supply chain issues associated with mRNA vaccines and other injectables – namely the cold or sub-zero storage required. The tablets also would not require administration by a medical professional, reducing the burden on health systems and offering a more attractive option for needle-phobic patients.
Above and beyond those benefits, clinical trials show that Vaxart’s COVID-19 vaccine has demonstrated a more robust immune response via mucosal antibodies by delivering both the spike proteins (S) and the virus’s nucleoprotein (N). Early results indicate the vaccine may offer longer protection against COVID-19 than what is currently available. Nucleoproteins are less likely to mutate and targeting them may offer protection against SARS-CoV-2 variants and even other coronaviruses.
The company announced in August that the US Food and Drug Administration (FDA) cleared its Investigational New Drug application for an S-only tablet.
Inovio – Needle-free Intradermal Delivery
Like the Vaxart COVID-19 vaccine, Inovio’s needle-free intradermal delivery of their candidate, INV-4800, would help overcome administration issues with the handheld smart device that delivers a DNA plasmid through the skin via a brief electrical pulse. In a Phase 1 study, only mild side effects were reported in five of the 40 participants. The trial results showed that participants had higher levels of antibodies against the coronavirus than people who received the Johnson & Johnson and Sinovac vaccines, which use adenoviruses.
The vaccine does require two doses, but it can last one year at room temperature and five years with refrigeration. Inovio has received authorization to conduct Phase 3 trials in Mexico, Brazil, and the Philippines as part of a global trial in partnership with China’s Advaccine Biopharmaceuticals.
It should be noted that another needle-free vaccine was recently approved for emergency use in India –Zydus Cadila’s DNA-based COVID-19 vaccine. ZyCoV-D is injected under the skin via a very narrow fluid stream that penetrates the skin. While being needle-free and easier to administer is a clear advantage, the downsides include that it requires three doses, recent reports suggest it will be priced significantly higher than the currently available vaccines, and the amount the manufacturer can export remains in question.
Vaxxinity – Offering the Flexibility of Synthetic Peptides
UB-612, the COVID-19 vaccine from Vaxxinity (a holding company consolidating vaccine development efforts of COVAXX and United Neurology) will be the first multitope protein/peptide-based vaccine and will only require standard refrigeration. It targets a critical antigen from the S protein, the receptor binding domain, which is believed to be necessary for the virus to attach to human cells. It also includes additional viral epitopes designed to promote B-cell and CD8+ T-cell memory responses. The manufacturer claims using synthetic peptides will allow them to swap target epitopes and amino acid sequences with relative ease, positioning them for a rapid response to variants of the SARS-CoV-2 virus.
Phase 1 testing in 60 adults demonstrated that it elicited a strong antibody response with no serious safety concerns and mild side effects. The company is evaluating the vaccine in Phase 2a trials in Taiwan and will continue with Phase 2 and Phase 3 trials in Brazil.
Valneva – Traditional Methods with Superior Results
Valneva’s vaccine candidate, VLA2001, uses an inactivated version of SARS-CoV-2 and two adjuvants that will help boost the body’s immune response. Using the entire virus (except for one protein) may make the vaccine more effective against variants, which have slight changes to their spike proteins. While there are other inactivated-virus vaccines in development, the others do not include adjuvants to improve the immune response. The company announced in September that it had recruited 300 volunteers in New Zealand for a Phase 3 trial to study the vaccine in participants age 56 and older.
The traditional manufacturing method may address one of the most surprising challenges in the delivery of vaccines, particularly in developed countries such as the United States, and that is the fear of the “unknowns” of mRNA technology. There has been no scientific evidence supporting safety concerns, but the perception continues to be a stumbling block in vaccination rates.
Potentially the first plant-based human vaccine, Medicago’s COVID-19 vaccine candidate, is in Phase 3 trials. Researchers at the Canada-based company use a relative of the tobacco plant that is modified to serve as a bioreactor, producing the virus-like particle that mimics the virus and activates the immune system. The vaccine would require two doses and is combined with GlaxoSmithKline’s pandemic adjuvant. The clinical trials started in Canada and the United States and will expand to 10 countries. The company recently announced that an early phase clinical trial will soon begin in Japan.
Bharat Biotech’s COVID-19 vaccine, Covaxin®, is awaiting emergency use approval from the World Health Organization (WHO). In addition, the manufacturer is currently working on BBV154, a two-dose intranasal vaccine that uses adenovirus to deliver the spike protein gene, that is entering a Phase 2 clinical trial in India. Early results show the vaccine stimulates a broad immune response in the nasal mucosa, where the viral infection takes place, and offers the potential for blocking infection and transmission of COVID-19.
Barriers Keeping Innovations from the Market
Will the potential to improve worldwide vaccination rates be enough to enable these medicines to reach the marketplace? A few things may get in the way. First, finding people to participate in clinical trials where they might receive a placebo instead of a vaccine can be challenging, especially in countries where other authorized vaccines are available. Second, the mRNA vaccines from Moderna and Pfizer have set a very high bar, demonstrating 94 to 95 percent efficacy in clinical trials.
It is yet to be determined if a lower-efficacy vaccine would be able to gain regulatory approval, and if approved, would there be market demand for them when there are “better” alternatives available. If early trial results do not meet high efficacy expectations, can these novel approaches that remove many of the barriers of mRNA vaccines be successful anyway? If so, will these new entrants provide a much-needed boost to global vaccination rates? The world is left to wait and see.
QPS is a CLIA-certified GLP- and GCP-compliant contract research organization (CRO) delivering the highest grade of discovery, preclinical and clinical drug research development services. Since 1995, it has grown from a tiny bioanalysis shop to a full-service CRO with 1,100+ employees in the U.S., Europe and Asia. Today, QPS offers expanded pharmaceutical contract R&D services with special expertise in neuropharmacology, DMPK, toxicology, bioanalysis, translational medicine and clinical development. An award-winning leader focused on bioanalytics and clinical trials, QPS is known for proven quality standards, technical expertise, a flexible approach to research, client satisfaction and turnkey laboratories and facilities. Through continual enhancements in capacities and resources, QPS stands tall in its commitment to delivering superior quality, skilled performance and trusted service to its valued customers. For more information, visit www.qps.com or email firstname.lastname@example.org.