When COVID-19 emerged at the end of 2019, and the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) genetic sequence was made publicly available in January 2020, the scientific community responded quickly, accelerating the production of new vaccines. Confidence in this endeavor was high, given that more than a decade of previous work had identified the spike protein as a promising vaccine target for both severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS). For both of these viral respiratory infections, inducing high levels of anti-spike protein neutralizing antibodies and T-cell responses provided protective immunity in laboratory viral challenge experiments.¹ On this basis, the scientific community of virologists, immunologists, and vaccinologists set off to produce vaccines that could deliver a SARS-CoV-2 spike protein or its receptor binding domain component to the human immune system.

Enthusiasm was especially high for advancing vaccines employing vesicular stomatitis virus (VSV) vector technology. Canada’s National Microbiology Laboratory and Merck & Co. used this strategy to develop a highly effective vaccine (VSV-EBOV) to prevent Ebola virus infection.² The VSV-EBOV was a spectacular success, with the ability to induce more than 90% protective immunity after a single immunization. Ultimately, VSV-EBOV saved thousands of lives and halted a frightening outbreak of Ebola virus infection in the Democratic Republic of the Congo (DRC) in 2019.³ An added benefit of the VSV-EBOV vaccination campaign is that it may have helped to promote stability and security in the region.

Surprisingly, however, the VSV vector technology was not effective for COVID-19. A disappointing Merck & Co. announcement in January 2021 reported that in phase 1 clinical studies, two VSV-SARS-CoV-2 spike protein vaccines were well tolerated but did not induce adequate immune responses. However, as the world now knows, two mRNA vaccines from Pfizer-BioNTech and Moderna were successful in inducing high levels of protection against COVID-19, and particularly against serious outcomes. In the meantime, other vaccine technologies have also advanced for COVID-19, including adenovirus-vectored vaccines, next generation whole-inactivated virus, and recombinant protein vaccines.⁴

A key lesson learned: there is no obvious way to predict ahead of time the best vaccine technology for any specific pathogen. VSV was effective for the Ebola virus but failed for SARS-CoV-2; similarly, the mRNA approach may or may not be widely successfully beyond SARS-CoV-2. Emphasizing that second point is essential to manage the public’s expectations, especially given the many optimistic predictions in the media and even among science policymakers that the mRNA vaccines will be transformative for or even revolutionize vaccine biotechnology.⁵

Along those lines, it is equally important to remember that while the two mRNA vaccines for COVID-19 have had an important impact on the COVID-19 pandemic in the global North, they have yet to reach the global South at anywhere near the same levels, contributing to huge inequities in COVID-19 vaccine access. While many cite the deep-freezer storage requirement for mRNA lipid nanoparticles as an access barrier, the reality is that freezer storage did not prevent the distribution of VSV-EBOV in the DRC. Instead, as there is for any emerging technology, there has been a steep learning curve for engineering and deploying mRNA vaccines at scale, as well as other new technologies such as the adenovirus-vectored or virus-like particle (VLP) vaccines.⁶ Oxford University and AstraZeneca were successful in transferring production expertise to Serum Institute of India and others. Ongoing attempts are underway to establish mRNA production hubs around the world. But, so far, quantities of COVID-19 vaccines are still insufficient to meet global needs. Conventional vaccine technologies, therefore, should not be overlooked during a pandemic, as many manufacturers already have the know-how, experience, and infrastructure to produce them en masse.

In response, the World Health Organization, under the leadership of Dr. Tedros  Adhanom Ghebreyesus, together with global agencies, including the innovative sharing facility COVAX, has made an effort to ensure the quality and regulatory control of the COVID-19 vaccines, especially the whole-inactivated virus vaccines from China. In addition, it supports the creation of new manufacturing hubs in the global South. However, considering the long timelines for building such local capacity, we need additional mechanisms now to scale production and make the vaccines available in the coming months.

For example, our Texas Children’s Hospital Center for Vaccine Development (Texas Children’s CVD) and Baylor College of Medicine are working with low- and middle-income country (LMIC) vaccine manufacturers to technology transfer a traditional recombinant protein vaccine produced through microbial fermentation in yeast.⁷ This approach, which has been used for decades to produce a highly safe and effective recombinant hepatitis vaccine, was shown to be highly successful against SARS in preclinical studies.⁸ The technology has been successfully transferred to India, Indonesia, Bangladesh, and elsewhere, where it is being produced at industrial scales and is being evaluated in the clinic. As a consequence, on December 28, 2021, CORBEVAXTM our vaccine co-developed with Biological E. Limited, received approval in India for emergency use.

Ahead of the next pandemic, it is essential that support for vaccine development is sustained to ensure that multiple vaccine technologies are made widely available. The vaccine inequities seen in the COVID-19 pandemic reminds us that producing exciting new vaccine technologies is not sufficient. It is equally urgent to maintain traditional technologies, ones that can be easily transferred and scaled up by vaccine producers globally. We must do both.

Preparing for the next pandemic will also require shifts in how vaccines are produced and who leads their development. The current vaccine ecosystem still depends heavily on multinational companies to advance innovations and provide safe and effective vaccines. But the fact that much of the global South still remains essentially unvaccinated, now two years into the COVID-19 pandemic, emphasizes the deficiencies of this approach. We must find ways to better engage existing vaccine manufacturers in LMICs and provide them with adequate support and supply chains so that they can expand their missions.

In parallel, we must look towards creating and building additional global production or development hubs for all the major vaccine technologies. This is true for both COVID-19-specific candidates and new disease targets. Such hubs must embrace both “shiny new toys,” e.g., mRNA, VSV vector technology, adenovirus-vectored vaccines, and VLPs emerging technologies, while also preserving the traditional approaches, e.g., whole-inactivated viruses and recombinant protein vaccines. We sometimes refer to these latter approaches as the “Matchbox cars,” a toy first made in the 1950s (Fig. 1). In addition to the pediatric recombinant protein vaccine for hepatitis B (mentioned above) and for COVID-19, we are also now evaluating this approach for a variety of parasitic infections and other neglected diseases of poverty.

Shiny new toys and Matchbox cars

Fig. 1. Shiny new toys and Matchbox cars. Left: A “Crash Bobby" (Qfix) for teaching robotics (Credit: KTB mechatronics). Right: A 1968/1969 Matchbox Ford pick-up truck (Credit: Frank Behnsen).

Investing in new vaccine development and production hubs goes beyond building plants and factories—they require maintaining cadres of well-trained scientists who are knowledgeable not only about production processes, but also quality control and assurance practices, together with detailed knowledge of the regulatory science. This also means establishing public-private partnerships between these chemical, manufacturing, and control (CMC) hubs and national regulatory authorities.⁹ Such partnerships should be built and funded so that they function in multiple regions and LMICs across the global South, especially in Africa, where almost no vaccine development or manufacturing is currently underway. This is not to overlook other world regions, including Latin America and southeast Asia, which also lag in many of these aspects. Finally, an expansion of vaccine science is required for research universities in the global South. There is urgency in establishing new doctoral and postdoctoral programs, together with training in vaccine quality practices and regulatory science so that a new generation of scientists can staff future CMC hubs in the global South.

A full description of the next-generation vaccine ecosystem goes beyond the scope of this article, but key elements include the need to maintain the capacity to produce a diverse portfolio of vaccine technologies, both old and new, while establishing or strengthening vaccine development and production hubs across the global South. Such actions are essential to achieve vaccine diplomacy and prevent the next pandemic.

Endnotes

1. Shibo Jiang et al., “Roadmap to developing a recombinant coronavirus S protein receptor-binding domain vaccine for severe acute respiratory syndrome,” Expert Review of Vaccines 11, no. 12 (2012): 1405–1413.
2. Francis A. Plummer and Steven M. Jones, “The story of Canada’s Ebola vaccine,” Canadian Medical Association Journal 189, no. 43 (2017): E1326–E1327; Keesha M. Matz, Andrea Marzi, and Heinz Feldmann, “Ebola vaccine trials: progress in vaccine safety and immunogenicity,” Expert Review of Vaccines 18, no. 12 (2019): 1229–1242.
3. Chad R. Wells, Abhishek Pandey, Alyssa S. Parpia, Meagan C. Fitzpatrick, Lauren A. Meyers, Burton H. Singer, and Alison P. Galvani, “Ebola vaccination in the Democratic Republic of the Congo,” Proceedings of the National Academy of Science 116, no. 20 (May 2019): 10178–10183.
4. Peter J. Hotez et al., “Global public health security and justice for vaccines and therapeutics in the COVID-19 pandemic,” EClinicalMedicine 39 (2021): 101053.
5. Antonio Regalado, “The next act for messenger RNA could be bigger than covid vaccines,” MIT Technology Review, February 5, 2021, www.technologyreview.com/2021/02/05/1017366/messenger-rna-vaccines-covid-hiv.
6. Hotez et al., “Global public health security.”
7. Jungsoon Lee et al., “Process development and scale-up optimization of the SARS-CoV-2 receptor binding domain-based vaccine candidate, RBD219-N1C1,” Applied Microbiology and Biotechnology 105, no. 10 (2021): 4153–4165.
8. Wen-Hsiang Chen et al., “Yeast-expressed SARS-CoV recombinant receptor-binding domain (RBD219-N1) formulated with aluminum hydroxide induces protective immunity and reduces immune enhancement,” Vaccine 38, no. 47 (2020): 7533–7541.
9. Hotez et al., “Global public health security.”