Will the Second Wave of COVID-19 Vaccines Have the Improved Properties Needed to End the Pandemic?

Will the Second Wave of COVID-19 Vaccines Have the Improved Properties Needed to End the Pandemic?

Mar 18, 2022PAO-03-022-NI-05

The rapid development, manufacture, and distribution of mRNA and viral vector vaccines against the SARS-CoV-2 virus has been nothing short of astonishing. These vaccines have done much to reduce the number of people suffering severe illness and death due to infection by this virus and its variants. They aren’t, however, sufficient to gain control over the pandemic. Fortunately, a new wave of vaccines is in development. The hope is that they will offer improved performance and protection.

What Does the Ideal COVID-19 Vaccine Look Like?

The ideal COVID-19 vaccine will have certain characteristics that contribute to its ease of use and effectiveness. Specifically, the next generation of COVID-19 vaccines should:1,2


  • Protect against current and future variants of SARS-CoV-2, regardless of infectivity and virulency, without experiencing a drop-off in efficacy for an extended period of time (annual booster shots would be acceptable);
  • Potentially protect against all coronaviruses;
  • Reduce the risk of virus transmission at a very high level, including from vaccinated people through the development of high levels of neutralizing antibodies that destroy the virus before it replicates;
  • Be available at a sufficiently low cost to be affordable even in poor nations; and
  • Be stable at room temperature to allow for easy storage and shipment.

Limitations of Existing Technologies

The first COVID-19 vaccines had a tremendous impact on the spread of the virus, but they also have limitations. All of the vaccines are fairly expensive despite unprecedented levels of government funding support, particularly for poorer countries. Low-to-middle income countries have needed to rely on financial support from programs such as the World Health Organization’s (WHO) COVAX initative.1

In addition, the mRNA vaccines in particular must be stored and shipped at very low temperatures, further complicating their distribution in parts of the world that lack infrastructure for cold-chain management. The inability to achieve high levels of vaccination around the world has allowed virus mutation and the emergence of new variants of the SARS-CoV-2 virus.2

While the initial vaccines have provided some level of protection against these different variants, that protection is reduced below the original levels and not guaranteed for future variants. Mutations in the genetic sequence of the spike protein from which the vaccines were developed can result in reduced efficacy.1

Furthermore, the short-lived immunity of current COVID-19 vaccines has resulted in increasing numbers of breakthrough cases in which vaccinated people become infected due to decreased presence of protective antibodies.2

Introducing mRNA Manufacturing to Africa

One immediate solution to addressing vaccine access issues is to enable local production of current vaccines to reduce storage and transportation issues and also lower costs. To this end, the WHO launched an mRNA tech-transfer hub in South Africa in June 2021.1 Afrigen Biologics and Vaccines South Africa proceeded to produce its own version of Moderna’s mRNA vaccine using publicly available information — and because Moderna has stated that it will not enforce its patent during the pandemic. A manufacturing plant is under construction, and the goal is to initiate clinical trials by the end of 2022. Ultimately, the WHO would like Afrigen to train other companies from different parts of the world.

Taking a Mixed-Dose Approach

Another approach to increasing the effectiveness of current COVID-19 vaccines is to administer the different available vaccines for the first, second, and third doses.3 Studies are underway to explore whether the mixing of vaccine types provides the same or better performance as when the same vaccine is given for all three doses. Preliminary results have been positive, particularly for people with suppressed immune systems. The ability to vaccinate people with whatever vaccine is available could also help increase vaccination rates in low-to-middle income countries where shortages of a particular vaccine often occur.

Second-generation mRNA Vaccines in Clinical Trials

Both Moderna and Pfizer/BioNTech have second-generation versions of their mRNA vaccines in clinical trials. Similarly, AstraZeneca has developed a new version of its viral vector vaccine. These updated vaccines are intended to offer greater protection against the Delta and Omicron variants.3

In late January 2022, Pfizer and BioNTech announced that clinical trials had been initiated to test a new version of their vaccine designed specifically to protect against the Omicron variant.4 One day later, Moderna announced a phase II study of its Omicron-specific booster candidate ( mRNA-1273.529).5 According to a recent report in Nature, limited preclinical animal studies with Omicron-specific boosters show that they offer little if no better protection than a third (booster) shot of the currently approved versions.6

CureVac, whose initial mRNA vaccine candidate failed to meet performance expectations, has teamed up with GlaxoSmithKline (GSK) to develop a different mRNA vaccine (CV2CoV) that can protect against multiple SARS-CoV-2 variants.7 Early animal studies have produced promising results, but submission for approval of the vaccine likely won’t happen until at least the end of 2022,8 as clinical trials were only announced in late November 2021.9

The U.S. Army’s Spike Ferritin Nanoparticle (SpFN) COVID-19 vaccine has also been shown, when formulated with two distinct adjuvants –– Alhydrogel® or Army Liposome Formulation containing QS-21 (ALFQ) — to induce robust innate immune activity driving polyfunctional spike-specific T cell response, and the vaccine could work against multiple variants in animal models.10 

Self-Amplifying mRNA Could be Better Yet

At least two companies are developing truly next-generation mRNA vaccines based on self-amplifying mRNA (saRNA) technology. Unlike the first generation of mRNA vaccines, which direct cells to make proteins that lead to antigen formation until they are degraded, self-amplifying mRNAs also make additional copies of those proteins, providing the potential for improved and longer-lasting immunity.3 It is also possible that doses could be smaller, and thus potentially lead to fewer side effects, as well as being cheaper.

AstraZeneca is investing in saRNA technology being developed by Imperial College London and commercialized by its spinout VaxEquity,11 which has an saRNA COVID-19 vaccine in a phase I clinical trial. Early data indicate that the vaccine generates a strong immune response.12 

Gritstone Bio’s saRNA candidate (GRT-R910) is designed to generate robust CD8+ T cell and strong neutralizing antibody responses, according to CEO Andrew Allen.1 It should therefore provide longer-lasting immunity, even in immunosuppressed individuals. The vaccine candidate is also based on not just the SARS-CoV-2 spike protein but also highly conserved viral proteins that are less susceptible to mutation, and therefore has the potential to provide protection against many different variants.3 Gritstone launched a phase I clinical study in the UK in late 2022.8 Early results from the trials, which are being conducted in collaboration with The University of Manchester and Manchester University NHS Foundation Trust, showed that, at a 10-fold lower dose, the level of antibodies produced was similar to that of current mRNA vaccines.13

A phase I/II booster study of Arcturus Therapeutics’ ARCT-154 and ARCT-165 investigational, next-generation, self-amplifying mRNA vaccine candidates targeting COVID-19 variants of concern is also achieving positive results.14 ARCT-154 and ARCT-165, when administered in low doses (5 mcg) at least five months following initial vaccination with Comirnaty® (the original Pfizer/BioNTech mRNA vaccine), yielded robust increases of 54- and 47-fold, respectively, in neutralizing antibody responses against the Omicron variant.

DNA Vaccines Could Offer Advantages over mRNA

Early interest in mRNA vaccines and therapeutics has been driven by the fact that mRNA functions in the cytoplasm and does not need to be delivered into the cell nucleus, which is more difficult. The instability of mRNA, however, has led some companies to take a second look at DNA vaccines, which are much more stable.  

Inovio Pharmaceuticals has been developing its DNA vaccine since the spike protein sequence was first released. Interim efficacy results from a phase II/III trial of its INO-4800 candidates are expected in mid-2022.15 Earlier study results have shown broad T cell responses and thus potential to protect against multiple variants. The trial is being conducted with Advaccine Biopharmaceuticals Suzhou, which holds exclusive rights to develop, manufacture, and commercialize INO-4800 within Greater China.

A brand-new entrant in the field of DNA vaccines is Alvea, a startup founded in January 2022 to develop scalable, affordable, shelf-stable SARS-CoV-2 DNA vaccines to reduce vaccine inequity and mitigate the risk of future global health threats.16 The firm’s first two vaccine candidates, including one that targets the BA.2 COVID-19 variant, are already undergoing preclinical testing and are expected to enter human trials as early as March 2022.  

Protein-Based Vaccines Coming Soon

Advances are not limited to mRNA. Several companies are developing vaccines based on more established approaches, most notably proteins. While these vaccines take longer to develop than mRNA products, they leverage well-known production processes, typically only require refrigeration for storage and transport, and can be much less expensive.2,3

Companies with more traditional protein-based COVID-19 vaccines include Novavax, Clover Biopharmaceuticals, Biological E, Medicago, Akston Bioscience, and VBI Vaccines, among others. Academic groups at the University of Saskatchewan and Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine also have candidates in clinical trials.

Novavax  submitted an emergency use application for its NVX-CoV2373 COVID-19 vaccine candidate (Nuvaxovid) to the World Health Organization (WHO) in late 2021.3 It is already approved for use in approximately 170 countires.2 Its formulation contains a new adjuvant — Matrix-M — harvested from the inner bark of the Chilean soapbark tree (Quillaja saponaria) and originally used by the company for the development of flu vaccines with enhanced antibody responses and cross-protection against multiple strains.8 In clinical studies, the candidate was shown to be effective against some variants.

Novovax has agreed to provide millions of doses of its vaccine to COVAX once they receive WHO authorization. The Serum Institute of India is producing doses for Indonesia and the Philippines, which have given regular or emergency approval to the Novavax vaccine.3

Clover Biopharmaceuticals in mid-January 2022 announced final efficacy data from a phase II/III trial of its COVID-19 vaccine candidate SCB-2019 (CpG 1018/Alum).17 The candidate, which contains Dynavax Technologies’ adjuvant CpG 1018, had a favorable safety profile and demonstrated 100% efficacy against severe COVID-19 and hospitalization caused by any strain of SARS-CoV-2. Clover is in the process of submitting conditional regulatory approval applications to the NMPA, the EMA, and the WHO, and, like Novavax, has already agreed to supply COVAX with millions of doses once it receives approval.3 

Medicago and partner GSK announced in late February 2022 that Health Canada granted approval for COVIFENZ®, their adjuvanted, plant-based, recombinant virus-like particle (VLP) COVID-19 vaccine.18 VLPs are thought to better mimic the behavior of protein fragments as they interact with the immune system.3 Medicago claims the vaccine produces much higher antibody titers than the currently available mRNA vaccines.8

VBI Vaccines is also developing a VLP-based COVID-19 vaccine with funding from the Coalition for Epidemic Preparedness Innovations (CEPI). In the phase Ia portion of a phase I/II study, enveloped VBI-2902 after two 5-µg doses, when adjuvanted with aluminum phosphate, induced neutralization titers in 100% of participants.15 The company is also developing a trivalent pan-coronavirus vaccine candidate (VBI-2901) that expresses the SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins, for which it expects to launch a first clinical study in mid-2022.

Akston Biosciences, meanwhile, announced in February 2022 that its room-temperature stable (for at least 6 months) adjuvanted protein subunit vaccine candidate (AKS-452) was generally well-tolerated and produced a 100% seroconversion rate in the 90 µg single-dose regimen as well as in the 45-µg and 90-µg two-dose regimens in a phase I trial.19 The vaccine comprises an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (RBD) antigen engineered to preserve effectiveness against viral variants. Akston claims that the vaccine is substantially less expensive than current COVID-19 vaccines due to the elimination of cold-chain requirements and production using its high-volume, low-cost manufacturing platform. A phase II study is planned to confirm the vaccine’s safety and efficacy.

GBP510 from SK Bioscience and GSK is being investigated in a phase II study involving more than 4,000 participants, with results expected in the first half of 2022.15 Interim phase I/II results were positive, with a 100% seroconversion rate and all participants receiving the adjuvanted, self-assembled nanoparticle vaccine candidate developing strong neutralizing antibody responses. SK is developing the antigen with the Institute for Protein Design at the University of Washington with support from the Bill and Melinda Gates Foundation and CEPI.

CEPI is also funding the development of subunit vaccine candidate CoVac–II at the University of Saskatchewan’s Vaccine and Infectious Disease Organization.7 In animal models, the candidate was found to function better than current COVID-19 vaccines. It is also effective against variants of concern.20 The researchers are focused on developing vaccines for lower- and middle-income countries and are launching mid-stage studies in Africa in unvaccinated individuals.7 

CORBEVAX, meanwhile, is under development by researchers at the Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine. This group has updated a vaccine previously created against SARS-CoV-1 in response to the 2003 SARS outbreak. In a large clinical trial, the new COVID-19 vaccine candidate, which also contains Dynavax’s CpG 1018 adjuvant,21 was found to be safe, well-tolerated, and more than 90% effective at preventing symptomatic infections.2 

CORBEVAX received an Emergency Use Authorization (EUA) approval from the Drugs Controller General of India (DCGI) at the end of 202122 and has been licensed patent-free to Biological E. Limited (BioE), which has also received support from CEPI. BioE has announced plans to manufacture at least 100 million doses per month starting in February 2022.23 Companies in Indonesia and Bangladesh have also licensed the technology, as has California-based ImmunityBio, which is building manufacturing capacity in South Africa and other countries in Africa.

Older Technologies Could Work, Too

A few companies have elected to develop more conventional vaccines against COVID-19. Examples include Valneva and Ocugen in collaboration with Bharat Biotech.

Valneva’s VLA2001 inactivated, adjuvanted whole virus vaccine candidate has been shown to neutralize the Omicron variant after three doses in a phase I/II study with 30 participants. In an earlier phase III trial, two doses of VLA2001 given as a primary vaccination were shown to induce superior neutralizing antibody levels and a broad T cell response.24 The company also has a clinical trial underway to evaluate the use of VLA2001 as a booster shot.25 It is submitting applications to the EMA, the UK Medicines and Healthcare products Regulatory Agency, and the National Health Regulatory Authority in Bahrain (NHRA) and hopes to receive regulatory approval in the first quarter of 2022.

Ocugen, meanwhile, is working to get regulatory approval of whole-virion, inactivated COVID-19 vaccine candidate formulated with a toll-like receptor 7/8 agonist molecule (IMDG) and Alhydroxiquim-II, an NIH-funded adjuvant discovered by ViroVax. Covaxin was initially developed by Bharat Biotech and the Indian Council of Medical Research, National Institute of Virology.15 It has already received emergency authorization in India and several other countries and is on the WHO’s list of authorized vaccines.26 In the United States, the FDA placed a clinical hold on Ocugen’s Investigational New Drug Application for Covaxin in November 2021, but that was lifted at the end of February, 2022, allowing the company to proceed with its planned phase II/III study. The company is also seeking approval for Covaxin in Canada.

Vaccines Designed for Oral and Nasal Delivery in Development

To increase the likelihood that people with vaccine hesitancy will ultimately decide to get vaccinated, some companies are focused on developing COVID-19 vaccines that can be delivered without an injection. Oral and nasal delivery are attractive alternatives and also offer the benefit of targeting the areas where the SARS-CoV-2 virus enters and is initially most concentrated in the body (mucosal linings of the nose and throat). These types of formulations, in addition to being easier to administer, also tend to be less expensive to manufacture and have been well-demonstrated to be effective (e.g., pediatric vaccines against polio and influenza).3 Storage and shipment of tablets also does not require any cold-chain infrastructure.

Companies developing oral vaccines include MigVax Ltd, which has funding from CEPI, Vaxart, DreamTec Research Limited, and U.S. Specialty Formulations (USSF) in collaboration with VaxForm. The candidate from MigVax, an affiliate of The Migal Galilee Research Institute, is an orally administered protein subunit vaccine tablet based on a chimeric protein designed to generate mucosal immunity, neutralizing antibodies in the blood, and a T cell response.3 In preclinical testing, MigVax-101 was shown to elicit neutralizing antibody production and cellular responses in mice and has also demonstrated efficacy in preclinical tests as a booster for previously vaccinated persons.27

Vaxart’s oral COVID-19 vaccine candidate (VXA-CoV2-1.1-S) is a viral-vector vaccine based on adeno-associated virus serotype 5 (AAV5) in a phase II trial with interim data expected in the first quarter of 2022.28 A coating protects the tablet until it reaches the lower small intestine, where the viral vectors are released and then infect epithelial cells, which produce the SARS-CoV-2 spike antigen and a double-stranded hairpin turn adjuvant. The company claims the immune response and T cells in this region afford a stronger immune response.

In preclinical studies, VXA-CoV2-1.1-S was shown to generate antibodies to the original COVID-19 virus strain and to the beta, delta, alpha, and gamma variants of SARS-CoV-2 in the serum and nasal mucosa of non-human primates (NHPs) after a single dose.29 The data, according to the company, suggests that this vaccine candidate may be able to induce cross-protective antibodies at the site of infection.

The oral vaccine developed by DreamTec Research is a genetically engineered Bacillus subtilis bacterial vector vaccine that expresses the receptor binding domain of the spike protein of the SARS-CoV-2 virus on its spore coat.30 The concept behind this approach is to generate vaccine-like activity (secretion of cytokines and generation of neutralizing antibodies) within the intestinal environment using a bacterium that is regarded as safe by the U.S. FDA. The company is looking for partners with which to conduct preclinical studies.

Ziccum is not developing its own COVID-19 vaccines but is seeking to apply its technology for air-drying vaccines to generate a dry powder version of Janssen’s COVID-19 (and other) vaccines.1,8 The powdered form is stable and can be stored and transported at room temperature. The company reported in December 2021 that it had successfully performed proof-of-concept studies for the use of its air-drying technology to produce thermostable dry powder vaccines across four major platforms used for COVID-19 vaccines — protein subunits (PS), viral vectors (VV), inactivated virus (IV), and VLPs.31

There has been little news on the USSF/Vaxform liquid oral COVID-19 vaccine candidate CoV2-OGEN1, a protein subunit vaccine, since USSF announced positive results for preclinical safety and immunological studies in May 2021.32 A phase I study with 45 enrolled participants is underway that will be completed in December 2022.33

The University of Oxford is also investigating an intranasal version of its approved injectable COVID-19 viral vector vaccine ChAdOx1 nCOV-19, which it commercialized with AstraZeneca.34 The phase I study is intended to assess the safety, tolerability, and immunogenicity of one or two doses of intranasal ChAdOx1 nCOV-19 in people that have not yet been investigated and as a booster shot for individuals that have received two prior doses via injection. It is expected to be completed in March 2022.35

In total, there are 12 intranasal COVID-19 vaccine candidates in clinical trials, including those based on viral vectors, subunit proteins, and live-attenuated viruses.35 Early evidence based on preclinical studies suggests that intranasal delivery may elicit stronger humoral and cellular immunity, including higher levels of S-specific neutralizing antibodies than intramuscular administration. Intranasal vaccines may also induce pan-reactive antibodies against multiple COVID-19 variants.

In addition to Oxford University/AstraZeneca, companies with viral vector–based intranasal candidates in clinical trials include CanSino/Beijing Institute of Biotechnology, Bharat Biotech, Tetherex Pharmaceuticals, Altimmune, Laboratorio Avi-Mex, S.A. de C.V., the University of Hong Kong, Xiamen University and Beijing Wantai Biological Pharmacy, CyanVac LLC, and Meissa Vaccines. Razi Vaccine and Serum Research Institute and Codagenix are developing protein subunit and live-attenuated virus vaccines, respectively.36

Delivery via Microneedle Patches a Possibility?

Another “needle-free” delivery mechanism being explored for COVID-19 vaccines is the use of microneedle patches. Such patches would have the advantages of room temperature storage and transport and easy application without the need for trained medical staff. They deliver vaccines using thousands of tiny needles that do not draw blood and are too small to initiate a pain response.3 More specifically, the vaccine is delivered to a layer of immune cells that resides just beneath the top layers of skin.34 

Researchers at the University of Queensland, in collaboration with Vaxxas, have developed a single-dose nanopatch vaccine in which the tiny spikes of the patch are coated with the vaccine.34 The high-density microarray patch (HD-MAP) delivers a SARS-CoV-2 spike subunit vaccine (HexaPro, developed at the University of Texas) directly to the skin. The vaccine has been shown to be thermally stable when applied to the patch and to generate enhanced cellular and antibody immune responses in a single dose in mouse models.37 In late October 2021, the collaborators were anticipating taking their HD-MAP COVID-19 vaccine into clinical studies, but nothing has been reported since.

Targeting Multiple Viruses in One Vaccine

Some research efforts are not restricted just to COVID-19. A few companies are seeking to develop next-generation vaccines that can prevent multiple infectious diseases in one shot.2 One of those is Moderna, which is working on a potential combination vaccine that offers protection against COVID-19, influenza, and RSV, which could potentially be on the market by fall of 2023, according to CEO Stéphane Bancel.38

Many Challenges to Overcome

Making progress on new vaccines at this time is not an insignificant task.8 Supply chain issues for critical raw materials continue and can be particularly problematic for smaller vaccine companies. Regulators will also no longer be using the emergency authorization pathway for new vaccines. New products will have to receive full approval through the traditional approval pathway. Finding infectious people willing to participate in clinical trials that have not been vaccinated and not exposed to the SARS-CoV-2 virus is also difficult more than two years into the pandemic.

Still Hoping for Real Solutions

Even though it has been more than two years since the emergence of the COVID-19 virus, nearly half of the world’s population — most of whom are located in South America, Africa, and Asia — have yet to receive even a first dose of a vaccine.8 On a positive note, as of mid-January 2022, 137 COVID-19 vaccine candidates were undergoing clinical trials, and an additional 194 candidates were in preclinical development.39 As of the end of November 2021, only eight had received emergency use listings (EULs) by the WHO, and six of those are distributed through the COVAX framework.3

The hope is that some of the vaccine technologies outlined herein will be efficacious and make it possible to expand access to COVID-19 vaccines to people around the world, regardless of location, by reducing their cost, eliminating the need for a cold chain, and eliminating concerns about needle sticks. There is also an expectation that next-generation vaccines against SARS-CoV-2 will haveincreased efficacy in terms of more robust and longer-lasting immunity against current and future variants.

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