Technologies for COVID-19 and innovative therapies: contemporary challenges Tecnologias para COVID-19 e terapias inovadoras: desafios contemporâneos Tecnologías para la COVID-19 y terapias innovadoras: desafíos contemporáneos PERSPECTIVAS PERSPECTIVES

Investments in drug or vaccine technologies to deal with the COVID-19 pandemic have consequences in the form of externalities, due to, indirect benefits in other areas related to the respective innovation 1. The United States alone has invested more than USD 11 billion in COVID-19 medicines and vaccines (USD 3.5 billion of which in research) 2. Global production capacity is estimated at 42 billion doses of COVID-19 vaccines in 2022, 20 billion of which originate from innovative technologies such as genetic vaccines 3. Thus, there may be impacts on access to treatments for other comorbidities using this same range of technologies. The recent literature has reported on the potential implications of medicines and vaccines innovations in COVID-19 for new vaccines against other infectious diseases or cancer 4. However, the potential of these biotechnological products was already expanding before the pandemic, mainly for rare diseases. Therefore, considering a broader landscape of innovations with impacts on public health, we highlight the recent approvals related to core technologies in innovative vaccines, with a brief analysis of antibody combinations in confronting COVID-19. The article thus addresses similar technologies to innovations for COVID-19 vaccines and medicines in major regulatory agencies. The degree of innovation for a single disease is unprecedented in the case of COVID-19. Incremental innovations may be relevant in the case of more consolidated technologies, including more traditional antibodies or vaccines. However, more innovative technologies can accelerate a biotechnological paradigm shift. Around the world, there are more than 2,300 patent applications for COVID-19 medicine and more than 100 for vaccines alone 5. The vaccine patents are complex processes that involve licensing and disputes across various countries 6. In addition, there are 331 treatment proposals and 260 vaccines in the pipeline 7. The pandemic onset thus accelerates progress and repositioning of technologies with the potential to impact prices, increase opportunities, and affect regulatory processes.


Introduction
Investments in drug or vaccine technologies to deal with the COVID-19 pandemic have consequences in the form of externalities, due to, indirect benefits in other areas related to the respective innovation 1 . The United States alone has invested more than USD 11 billion in COVID-19 medicines and vaccines (USD 3.5 billion of which in research) 2 . Global production capacity is estimated at 42 billion doses of COVID-19 vaccines in 2022, 20 billion of which originate from innovative technologies such as genetic vaccines 3 . Thus, there may be impacts on access to treatments for other comorbidities using this same range of technologies.
The recent literature has reported on the potential implications of medicines and vaccines innovations in COVID-19 for new vaccines against other infectious diseases or cancer 4 . However, the potential of these biotechnological products was already expanding before the pandemic, mainly for rare diseases. Therefore, considering a broader landscape of innovations with impacts on public health, we highlight the recent approvals related to core technologies in innovative vaccines, with a brief analysis of antibody combinations in confronting COVID-19. The article thus addresses similar technologies to innovations for COVID-19 vaccines and medicines in major regulatory agencies.
The degree of innovation for a single disease is unprecedented in the case of COVID-19. Incremental innovations may be relevant in the case of more consolidated technologies, including more traditional antibodies or vaccines. However, more innovative technologies can accelerate a biotechnological paradigm shift. Around the world, there are more than 2,300 patent applications for COVID-19 medicine and more than 100 for vaccines alone 5 . The vaccine patents are complex processes that involve licensing and disputes across various countries 6 . In addition, there are 331 treatment proposals and 260 vaccines in the pipeline 7 . The pandemic onset thus accelerates progress and repositioning of technologies with the potential to impact prices, increase opportunities, and affect regulatory processes.

Technologies for COVID-19 products
Pharmacological products for COVID-19 are classified as either treatments or vaccines. Regarding medicines, antibody development accounts for 35% of current trials. From 85 antibody therapies for COVID-19, 50 are in various clinical phases and 35 in the preclinical phase. In addition, 35 therapies are being assessed, besides another 35 antivirals. In other innovative therapies, six RNA-based treatments correspond to various mechanisms in RNA vaccines. Other treatments include devices, nanoparticles, peptides, and immunoregulators 7 .
The vaccines can be included in four main categories of technologies: virus, protein, viral vector, and nucleic acid, with significant differences in their mechanisms of action and production processes 8 . The scientific effort has resulted in radical innovations in modified viral vector and messenger RNA vaccines 9 .
Genetic vaccines (viral vector or nucleic acid vaccines) mimic the actual viral infection, stimulating the T-cell humoral response. Most of the viral vector vaccines use human adenovirus vectors. Since the incidence is high, the Oxford/AstraZeneca (United Kingdom) vaccine uses a chimpanzee adenovirus as the vector for stimulating the immune system 8 .
Even though knowledge from similar previous products reduces current uncertainties in development, the production process, and adverse events, the speed in the development of innovative products favored their initial approvals 7 .
Concerning medicines, monoclonal antibodies are also promising technologies for COVID-19. In this case, the innovations use a mixture of two or more monoclonal antibodies, a combination generated from mice and infected human cells, seeking to avoid escape due to viral mutations 10 .

Similar innovative therapies and technologies for COVID-19 products
Various products have already been registered using similar technologies as vaccines developed for COVID-19. In addition to proteins and subunits, available in several medicines, nucleic acids and viral vectors are also present in some recent approvals of RNA, genetic, or cell therapies (Box 1). The degree of innovation differs in the case of gene or cell therapies, called advanced therapies by some regulatory agencies, with different approval processes 11 .
Gene therapies involve treatments using genetic material. Cell therapies transfer cells, which can be autologous, heterologous, or umbilical cord stem cells; they are also called gene therapies if they are genetically modified outside the patient's body. Based on this definition, since 2003, various regulatory agencies have approved 10 products classified as gene therapies, some of which were subsequently removed from the market. Various gene therapies are currently in the pipeline, many of in clinical trials, and estimates point to 30 to 60 new products of this type by 2030 12 .
RNA therapies can also be classified as advanced therapies. They usually do not require viral vectors, but the latter may be used, as in the case of nusinersen. As shown in Box 1, nine medicines have been approved with RNA technology, seven of which with antisense RNA. Only four medicines have been approved with RNA interference technology and one drug with aptamer RNA 13 .
The case of monoclonal antibodies includes incremental innovations, as products with more than one type of antibody, called polyclonal or multiclonal. The first such combination dates to 2015, and since then, many other immunotherapy regimens have been launched on the market. However, combinations for more than one target structure are recent, such as the mixture of three antibodies approved for Ebola in 2020 by the U.S. Food and Drug Administration (FDA) 14 . The production process for monoclonal antibodies is more consolidated. A study from 2018 found 34 antibodies registered in Brazil, divided into seven categories according to the activating receptors, representing an established technology 15

Challenges
These production processes and technologies related to advanced therapies bear similarities to vaccines under development for COVID-19. The processes share many inputs and operational production equipment.
The vehicles for advanced therapies present significant scientific externalities. RNA, lipid nanoparticles, polymers, or conjugates can offer therapeutic advantages for other drug classes. Meanwhile, adenoviruses are more commonly used for cancer vaccines and therapies, due to the immunogenic response, besides the shorter duration and higher expression 16 . Before the enormous progress against COVID-19, there were no widely registered vaccines with adenoviruses (only one Russian vaccine for emergency use and a Chinese cancer vaccine) 17 .
Subsequently, the knowledge of mechanisms of action represents a major improvement. Advanced therapies are frequently applied to rare diseases, due both to the regulatory incentive and as preferential targets for genetic point mutations, more easily determined than in the case of complex diseases that involve multiple genes 11 . Hence, although advanced therapies currently compete with vaccines for materials and production capacity, the long-term technological horizon points to potential progress for both.
The main challenge involves the high prices of advanced therapies. Estimates for the development of new medicines exceed billions of dollars, based on industry data 18 . In the case of rare diseases, the recovery of this investment occurs in a very small number of patients, and the initial registrations are limited to high-income countries. Although scaling up and improvements in production technology can help reduce costs, cooperation and solidarity in access are essential for more equitable and fair prices for countries.
Analogously, monoclonal antibodies can also benefit from the global production scale, reducing costs and allowing recovery of Research & Development investments with more favorable prices, with the expansion of access in the world, including governments in peripheral countries that could serve their population with lower budget expenditures.
In Brazil, recent approvals by the National Committee for Health Technology Incorporation (CONITEC) for nusinersen, with expanded use, result in a budget impact of more than BRL 2 billion (USD 400 million) by 2025 19 . Although Health Technology Horizon Scanning reveals few advanced therapies 20 , we observe a much broader range of medicines in this scope recently approved in the international setting. Accordingly, the relations between vaccine technologies with expanded production capacity and access allow forecasting this supply acceleration in the coming years.
Most innovations (Box 1) are for treatments of rare diseases. Brazil's National Policy on Comprehensive Care for Persons with Rare Diseases initially implemented 15 molecular biology and cytogenetic tests and immunoassays, besides genetic counseling and three diagnostic procedures. In Brazil, there are currently 36 Standard Treatment Guidelines for Rare Diseases 21 . However, 90% of lawsuits involve orphan diseases, and the number of Brazilians diagnosed with rare diseases increased 150% in the last four decades 22 . In 2018, the Brazilian Federal Government spent BRL 1 billion (USD 200 million) on medicines obtained by patients through lawsuits. If we add states and municipalities, the total reaches BRL 7 billion (USD 1.4 billion) a year 23 . Due to knowledge gaps on this topic, research agencies have recently issued calls for projects to research rare genetic diseases and innovative platforms in advanced therapies 24 .
Although the scope of this article is the possible influence of vaccines and some treatments, technologies used for COVID-19 in public health are not limited to this. The increase of testing capacities, apps for notifying exposure, and user-friendly contact-tracing technologies would be epidemiologically relevant for orienting health system needs, especially for infectious diseases.

Final remarks
The opportunities for global cooperation are similar for COVID-19 therapies and vaccines and innovative therapies for personalized medicine. However, the increase in health expenditures worldwide may exceed the payment capacity of individuals, insurance companies, and health systems. The possible affordability on various countries would mitigate restrictions in access, as discussed in forums of the United Nations agencies and included in the Sustainable Development Goals.
The pandemic has highlighted the divergence between solidarity to ensure the right to universal health and market competition. The competition for health products is not an isolated issue from prevailing geopolitical and economic arrangements. The sustainability of increasingly personalized treatments challenges healthcare supply and demand in countries with universal systems. In Brazil, this share of the population benefited by these advanced therapies tends to grow, and a better response to the scenario by the Brazilian Unified National Health System (SUS) involves adequate financing and multilateral cooperation to allow scientific progress accesses for the population.

Contributors
F. V. Leineweber contributed to the search for references, data collection and preparation of the text. J. A. Z. Bermudez contributed to the writing and revision of the text.