Immediately after the genetic sequence of the SARS-CoV-2 virus was reported, numerous companies and academic research groups began working on vaccines to prevent COVID-19. New genetic vaccine technologies made it possible for the first candidates to receive emergency use authorizations in record time, affirming their potential for future pandemic solutions. There are many others that are still undergoing clinical trials.
Numerous Anti-COVID Vaccine Strategies
Fighting a pandemic caused by a virus like SARS-CoV-2 takes many different types of vaccines. Some people cannot tolerate vaccines with certain excipients. In some regions, it isn’t possible to offer vaccines that must be stored at very low temperatures, because there is no pharmaceutical cold chain established. Different types of vaccines have different modes of action, which helps ensure ongoing effectiveness.
Many different vaccines are being developed against SARS-CoV-2, including live attenuated, recombinant protein (subunit, virus-like particle, etc.), viral vector, DNA, and RNA products.1 Knowledge gained during the development of vaccines for other β-coronaviruses, including the ones that cause SARS and MERS, has been leveraged.
Live viruses are weakened via codon deoptimization or mutation of the E protein and are known to produce a strong immune response. Recombinant protein vaccines use a portion of the virus protein (or proteins) to elicit the immune response, but typically require the use of an adjuvant to achieve sufficient immunogenicity.
Viral vectors promote a strong T cell response but can cause an immune response to themselves, which causes difficulty with long-term performance and the use of booster shots. DNA and messenger RNA (mRNA) vaccines are genetic vaccines that cause cells to express antigens against SARS-CoV-2.
Vaccines based on attenuated viruses have been used for decades and are safe and effective, but are not suitable for people with compromised immune systems and take many years to develop and commercialize. Recombinant protein vaccines based on the SARS-CoV-2 spike (S) protein have been the preferred solution in the last few decades. They eliminate the need to work with live viruses but still take several years to develop and typically require the use of adjuvants to generate sufficient immunogenicity.
A few viral vector vaccines have been approved for veterinary use and one for use in humans against Ebola (Johnson & Johnson (J&J)) received marketing authorization in Europe and the United States in 2020. J&J and AstraZeneca/Oxford University have received emergency use authorizations (EUAs) in the United States and Europe, respectively, for their viral vector COVID-19 vaccines. Russia’s Sputnik V is also a viral vector vaccine.
DNA vaccines have been approved for use in animals, but none have yet been approved for use in people. The Pfizer/BioNTech and Moderna mRNA vaccines against COVID-19 were the first to receive any type of approval (both were granted EUAs).
Traditional vaccine developers are all working on vaccines against COVID-19, both live virus and recombinant protein versions. Many have also been involved in the newer genetic vaccine technologies, if not internally, then through partnerships with academic groups or emerging biotech companies.2
In addition to J&J, AstraZeneca, and the Gamaleya National Center of Epidemiology and Microbiology in Russia, CanSino Biologics and ReiThera (previously Okairos) are two firms developing viral vector vaccines. Emerging company Inovio and established vaccine maker Sanofi Pasteur are leaders in the development of plasmid DNA-based anti-COVID-19 vaccines. Other companies besides Pfizer and Moderna focused on mRNA vaccines against include CureVac and Translate Bio.
By early 2021, more than 80 clinical trials had been imitated, with 18 vaccines reaching later-stage development (phase II/II or III) and four receiving approval of some type in the United States and/or Europe.3
Vaccine Development at Light Speed
That several vaccines could be developed, receive emergency authorization, be manufactured in large quantities, and be given to millions of people within a year of identification of the SARS-CoV-2 sequence is nothing shorty of amazing – “a remarkable success story” and “an extraordinary accomplishment,” according to Anthony Fauci, the director of the U.S. National Institute of Allergy and Infectious Diseases within the National Institutes of Health.4
Fauci attributes part of this success to precious work on vaccine platform technologies against coronaviruses and other viral pathogens, particularly RNA-based solutions, and advances in structural biology tools for designing optimum antigens.4 A study of the literature regarding COVID-19 vaccine efforts also revealed that recent advances in basic scientific understanding, combined with established development strategies and optimization of regulatory pathways, contributed to the accelerated development and commercialization timelines.5
Platform vaccine technologies have been key to the ability for developers of mRNA, DNA, and viral vector vaccines to move rapidly into the clinic with candidate products. For instance, BioNTech’s mRNA technology allows for a candidate to be designed within a few hours of receiving the sequence of the target virus.6 A DNA template for the RNA can be produced within days, and the first GMP manufacturing batch of clinical material within just 3 months of starting a project.
Manufacturing platforms have also been important. Pall employed its standard platform for adeno-associated virus (AAV) vector manufacturing that leverages standard single-use manifold designs when developing a process for the production of AstraZeneca’s COVID-19 vaccine.7 Rather than the typical one year to go from customer engagement to implementation, validation, and start-up, Pall was able to transfer a commercial process to AstraZeneca’s many contract manufacturers around the world in just 8 weeks.8
Extensive effort by thousands of pharmaceutical scientists and production engineers has been another part of the story. Not only did the right mRNA and viral vectors need to be designed and developed, efficient manufacturing processes had to be established and implemented. Improvements have been ongoing as companies strive to make hundreds of millions of doses as quickly as possible without risking quality or safety. Engineers at Pfizer, for instance, have reduced the time to produce a batch of 1–3 million doses of its mRNA vaccine from 110 to 60 days.9
Government support was another critical factor enabling those millions of doses of vaccines to be produced, distributed, and administered to people so quickly. Financial investment during development, advanced purchases of doses, and facilitation of arrangements between developers and suppliers from contract manufacturing and research organizations to equipment and consumable suppliers around the globe provided through Operation Warp Speed were all critical.10
Funding, for instance, enabled vaccine developers to secure contract manufacturing capacity early on.10 The US government even contracted some of the capacity directly, including capacity at other major pharmaceutical companies. Government dollars also went to biopharma suppliers, such as Cytiva, Corning, and ApiJect Systems, among others, to increase their ability to produce cell culture media and bioreactors, syringes, glass vials, and needles.
Charitable groups also played a role in facilitating vaccine development. The Coalition for Epidemic Preparedness Innovations (CEPI), Gavi, and the COVAX facility are examples of groups that provided seed funding to several smaller biotechs developing COVID-19 vaccines. Collaborations between pharma companies, such as Novavax, which is developing a subunit vaccine, with Takeda and the Serum Institute of India and CSL with AstraZeneca, has helped address capacity issues in many locations around the world where biopharma manufacturing capability is limited.10
Addressing Longevity and Variant Concerns
Shortly after the EUAs were granted to Pfizer/BioNTech and Moderna, new notable variants of the SARS-CoV-2 virus were detected in multiple regions of the world. These variants were notable because they had mutations in key parts of the viral sequence that caused them to be much more transmissible and potentially more deadly. They also raised concerns about the level of protection the authorized vaccines could provide if these variants became the dominant strains. These concerns were added to the uncertainty that existed regarding the length of time the new mRNA vaccines would provide a high level of protection.
Additional clinical trial data and real-world evidence has helped allay these fears for both mRNA vaccines. Pfizer/BioNTech published additional data for people who have been fully vaccinated with their mRNA vaccine in early March 2021.11 The real-world evidence was collected in Israel by the Israel Ministry of Health and confirmed dramatically lower COVID-19 disease incidence rates and prevention of asymptomatic SARS-CoV-2 infection.
Pfizer and BioNTech also reported on April 1, 2021 that, up to six months following the second dose of their mRNA vaccine, no serious safety concerns were observed, and the vaccine exhibited 91.3% against COVID-19.12 It was also found to be 100% effective in preventing severe disease and in preventing COVID-19 cases in South Africa, where a particularly virulent new strain erupted.
In February 2021, the two companies announced a new arm of their phase I/II/III trial to evaluate a third dose of their COVID-19 vaccine.13 They were also discussing an additional registration-enabling study using an mRNA vaccine with a variant sequence that would enable rapid modification of the vaccine so it would be useful against new strains that may emerge.
Moderna, meanwhile, reported in late January 2021 that results of in vitro neutralization studies of sera from individuals vaccinated with its COVID-19 vaccine confirmed activity against emerging strains of SARS-CoV-2.14 The company also announced that it would be initiating an additional clinical study to determine the value of administering an additional booster dose. In early April, the company published antibody persistence data out to six months following the second dose of its COVID-19 vaccine, confirming that the vaccine continued to provide strong protection.15
In early March, Moderna announced that, as an amendment to its ongoing phase II clinical study, the first participants were dosed with the company’s modified COVID-19 vaccines designed to address the potential need for booster vaccine candidates that can increase the breadth of response to emerging variants with key receptor-binding domain (RBD) mutations.16 A few days later Moderna announced that it had dosed the first participants in a phase I study evaluating its second-generation COVID-19 vaccine, a potential refrigerator-stable candidate.17
Some Issues to Overcome
The accelerated rate of development and early authorizations have not proceeded without some difficulties. Perhaps the biggest issue is related to the viral vector vaccine from Johnson & Johnson.18 In mid-April, the FDA and the Center for Disease Control, “out of an abundance of caution,” recommended a pause in the administration of the vaccine following the occurrence of six cases in the United States of a rare and severe type of blood clot in women after receiving it. A decision on whether its use would be resumed was expected by April 23rd.19
There have been manufacturing issues as well. Production problems at contract manufacturer Novasep meant AstraZeneca could only provide 40% of the doses promised to the EU in Q1 2021.20 Meanwhile, Pfizer had to reduce shipments of its vaccine to Europe and Canada while it expanded capacity at its Brussels manufacturing site, where all COVID-19 vaccine doses going to countries other than the United States are made. Separately, hacked documents from the EMA revealed some issues with early commercial batches of the Pfizer/BioNTech vaccine, although the regulatory agency indicated that the release documents were modified in a manner designed to raise concerns about the vaccine.21
It shouldn’t come as a surprise that there have been manufacturing issues, given the speed at which these novel vaccines have been developed and produced. Manufacturing processes for all types of vaccines are highly complex, which makes production at large scale challenging, even without it being the first time for a new technology and intense time pressures.
For mRNA vaccines, the most challenging step is the encapsulation of the mRNA into lipid nanoparticles (LNPs).22 Both the Pfizer/BioNTech and Moderna mRNA vaccines use a mixture of common and proprietary, specialized lipids and proprietary mixing technologies to generate these nanoparticles. The lipids are manufactured and formulated by suppliers with expertise in lipid synthesis. Given the number of doses needed, only the largest contract manufacturers — and other pharmaceutical manufacturers — can provide suitable capacity.
Viral vector manufacturing remains highly inefficient, as the technology is still relatively new, and manufacturers are still working to identify the most important critical quality attributes that impact product quality and establish standardized processes and design fit-for-purpose production equipment and purification techniques that provide high and consistent yields.23
Supply issues are another concern, from raw materials like the lipids needed for mRNA vaccines to the plasmid DNA for viral vector production and the adjuvants used in the formulation of subunit vaccines.22,24 Single-use bioreactor bags and other consumables are already delaying some vaccine production,23 most notably for Novavax.25
Operation Warp Speed members at the Department of Defense and Health and Human Services are working to address these supply chain and other manufacturing issues, as well as tackling the shortage of skilled labor by expediting visa approvals for key technical personnel.26
Outsourcing and Unusual Collaborations Address Capacity Issues
The large numbers of doses — billions — required to fully vaccinate the global populations against COVID-19 requires production on an unprecedented scale that cannot be met by vaccine developers by themselves. Outsourcing to contract manufacturers has been critical to the vast ramp up of manufacturing.
Indeed, contract manufacturers both large and small are supporting COVID-19 manufacturing efforts. Catalent and Lonza — two of the largest service providers — are producing Moderna’s mRNA product. In March 2021, Moderna added additional fill/finish capacity through an agreement with Baxter BioPharma Solutions.
Catalent is also supporting J&J with fill/finish capacity. J&J has additional agreements with other contract manufacturers, including Emergent BioSolutions. AstraZeneca established agreements with approximately 20 contract manufacturers to produce its viral vector vaccine. Inovio is also relying on a number of contract manufacturers, including VGXI, Richter-Helm BioLogics, and Ology Biosciences to produce millions of doses of its investigational DNA vaccine.
Both Pfizer/BioNTech and Moderna have established additional long-term partnerships with suppliers of the lipids required to encapsulate their mRNA active substances to enable effective delivery into human cells. Companies providing these services include Croda, Acuitas Therapeutics, AMRI, and Cordon Pharma, among others.
Even outsourcing capacity isn’t sufficient, though. Many pharma companies that don’t have their own approved COVID-19 vaccines are also supporting the production of the approved or expected-to-be-approved options. In late January 2021, both Sanofi and Novartis entered into agreements to produce and supply the Pfizer/BioNTech COVID-19 vaccine in Europe.27
At the time, Novartis was also in talks with other COVID-19 vaccine and therapeutic developers about possible production support for their products, while Sanofi was working with GlaxoSmithKline (GSK) to develop two COVID-19 vaccine candidates.26 GSK in March 2021 also committed to fill/finish 60 million doses of the Novavax subunit COVID-19 vaccine at a facility in England once the candidate receives approval.28
Moderna has also sought support from other pharmaceutical companies. In mid-April, the company was reported to be in talks with Nexus Pharmaceuticals regarding production of its mRNA vaccine at Nexus’ new Wisconsin facility, which has the capacity to process and fill 30 million doses a month.29
J&J, meanwhile, will receive COVID-19 vaccine manufacturing support for the vaccine substance and fill/finish from two Merck facilities, a deal brokered by the Biden administration.30 In addition, in mid-April, Takeda, J&J, and IDT Biologika announced that Takeda would forego use of three months of booked capacity at IDT in order for the contract manufacturer to support fill/finish of J&J’s COVID-19 vaccine.31
Vaccine developers and contract manufacturers have also been investing to expand capacity at a record pace. By March 2021, Pfizer/BioNTech, Moderna, and J&J were expected to produce 132 million doses that month — three times as much as in February.32 As of March 3, Airfinity estimated that 413 million doses had been produced, with 141.6 million manufactured in China, 103 million in the United States, 70.5 million in Germany and Belgium combined, and 42.4 million in India.33
Current Candidate Landscape
Another study by Novateur Ventures compared 12 COVID-19 vaccines that had at least announced if not initiated phase III clinical trials as of early November 2020.34 The vaccines included the now authorized Moderna and Pfizer/BioNTech mRNA products; the viral vector vaccines from AZ, J&J, CanSino Biologics, and Gamaleya Research Institute; recombinant protein-based vaccines from Novavax and Medicago; and inactivated virus vaccines from three different Chinese conglomerates and one Indian company.
The vaccines were all evaluated against a "harmonized" target product profile (TPP) version of guidance from the World Health Organization, the Coalition for Epidemic Preparedness Innovations (CEPI), and the Center for Biologics Evaluation and Research (CBER). Key factors considered were efficacy, dosing regimen, logistics, safety, and target price/accessibility.
All but two of the vaccines require two doses, so the dosing regimen was not really a differentiating factor. The mRNA vaccines outperformed the other vaccine technologies with respect to efficacy, but ranked lowest due the need to store and transport them at very low temperatures. With respect to safety, the inactivated viruses ranked highest, while the viral vector vaccines ranked lowest. Pricing results were mixed, given the early production stages.
According to the RAPS COVID-19 Vaccine Tracker, as of April 15, 2021, 13 COVID-19 vaccines had received authorization for use around the world, including products from Pfizer/BioNTech, Moderna, AZ, and J&J in the West; Gamaleya Research Institute, the Federal Budgetary Research Institution State Research Center of Virology and the Biotechnology, and Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products in Russia; Sinovac, Beijing Institute of Biological Products/China National Pharmaceutical Group (Sinopharm), CanSino Biologics, and Anhui Zhifei Longcom Biopharmaceutical/Institute of Microbiology of the Chinese Academy of Sciences in China; and Bharat Biotech/ICMR in India.35
An additional 60 COVID-19 vaccine were in phase I–III clinical trials or were in earlier phases of development but showing significant promise35 (Note: the list includes additional clinical trials for already approved vaccines, some of which are highlighted above.) The furthest along were recombinant protein vaccines from Novavax, Medicago, and the Center for Genetic Engineering and Biotechnology; DNA vaccines from Zydus Cadila and Inovio Pharmaceuticals; an mRNA vaccine from CureVac/GSK; viral vector vaccines from Immunity Bio/NantKwest and ReiThera/Leukocare/Univercells; a live attenuated vaccine from a research collaboration including Massachusetts General Hospital; and a multiple peptide-based vaccine from Vaxxinity.
Both Pfizer/BioNTech and Moderna are working to develop packaging solutions that will ease distribution challenges and increase access to their products, which require low-temperature storage. For instance, in late March 2021, EMA approved storage of the Pfizer/BioNTech vaccine at –25 °C to –15 °C for a total of two weeks based on new stability data.36 Moderna, meanwhile, garnered approval from the FDA for filling of up to 15 doses per vial of its COVID-19 vaccine in early April. The agency also authorized that the company’s vaccine could be kept up to 24 hours at room temperature once removed from the refrigerator.37
Concerns remain, however, about the ability to achieve widespread vaccination in certain parts of the world that lack extensive healthcare infrastructure.38 In particular, there has been a push by government leaders and international health officials to implement vaccine manufacturing in Africa where the fewest people have been vaccinated and there is currently no domestic production capability outside of South Africa.
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Keown, Alex. “Pharma Industry Comes Together to Support Manufacture of COVID-19 Vaccines.” BioSpace. 29 Jan. 2021.
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Powell, Anita. “African Experts Urge Local COVID-19 Vaccine Manufacturing.” Voice of America News. 12 Apr. 2021.