Materials and Methods
This review utilized a qualitative, narrative-based design tailored to explore national policy environments, innovation systems, and commercialization strategies for vaccine development in 4 LMICs. Although the study draws on a broad range of peer-reviewed and gray literature, a systematic review methodology was not applied. This decision reflects both the heterogeneity of source types (e.g., policy documents, regulatory data, and institutional reports) and the conceptual emphasis on institutional arrangements and policy frameworks rather than clinical or epidemiological outcomes. A systematic review was not feasible due to the diversity of document types and the policy-focused scope of inquiry. Instead, a structured, replicable 4-step framework was implemented to ensure methodological rigor and transparency.
Literature Selection
A comprehensive search of academic databases—including PubMed, Scopus, and Web of Science—was conducted to identify scholarly publications on vaccine innovation, technology management, and commercialization in LMICs. Special emphasis was placed on Brazil, Cuba, India, and Iran, given their documented efforts to develop and manufacture COVID-19 vaccines domestically. Parallel searches of gray literature were performed, focusing on reports issued by ministries of health, regulatory authorities, multilateral agencies, and national pharmaceutical institutions. These materials offered contextual and institutional insights not captured in academic sources [
4–
9].
A structured narrative approach was used, combining targeted searches in PubMed, Scopus, Google Scholar, and World Health Organization (WHO) repositories with official country sources published between 2020 and 2023. While systematic reviews offer broader generalizability, such an approach was unsuitable due to documentation heterogeneity, incomplete peer-reviewed coverage, and the highly context-specific nature of innovation pathways. Instead, a curated narrative synthesis was better aligned with the objective of identifying policy and implementation differences across cases.
In total, 123 peer-reviewed records were initially identified, along with 23 additional sources from institutional and governmental repositories. After removing duplicates and screening abstracts, 63 records underwent full-text review, of which 48 met the eligibility criteria for detailed synthesis. An overview of the selection process is presented in
Figure S1.
To minimize selection bias in the gray literature, only documents issued by official institutions (e.g., ministries of health, regulatory agencies, or WHO-affiliated bodies) were included, and these were triangulated against academic sources or public datasets when feasible. The inclusion of diverse literature types was intended to capture under-documented institutional mechanisms while maintaining credibility.
Framework Design
A conceptual framework was constructed to structure the comparative analysis, drawing on established models that examine the relationship between innovation systems, technology progression, and institutional mechanisms.
The national innovation system (NIS) theory, which evaluates how formal institutions, public agencies, and policy networks interact to generate and diffuse innovation across national boundaries [
10,
11].
The sectoral innovation system (SIS) perspective, which emphasizes the specific actors, technologies, and institutional arrangements within the vaccine sector, offering a sector-focused lens for cross-country comparison.
The technology readiness level (TRL) model, which provides a structured means of mapping the progression of technologies from basic research through clinical development to large-scale deployment [
12–
14]. In the context of vaccine development, TRL stages can be summarized as follows: (1) TRL 1–3: Fundamental research—antigen discovery, mechanism studies; (2) TRL 4–5: Preclinical studies and early translational steps, such as formulation and initial human safety testing (e.g., phase I trials); (3) TRL 6–7: Expansion into phase II and early phase III trials, refining good manufacturing practices (GMP) processes and immunogenicity profiling; (4) TRL 7–8: Regulatory interaction, dossier submission, and conditional approvals; (5) TRL 8–9: Large-scale manufacturing, full licensure, and deployment.
Together, these perspectives support a comparative analysis across technical, institutional, and regulatory dimensions, with particular emphasis on how sectoral structures shape national innovation performance.
Figure 1 illustrates this integration by aligning vaccine development stages with TRL milestones and the institutional interactions most relevant to LMIC contexts.
While the SIS framework highlights industry-specific dynamics, this study prioritizes the NIS perspective to capture the broader institutional, regulatory, and public health interactions underpinning national vaccine responses during a global emergency. The NIS approach enables cross-country comparisons that account for policy-driven innovation capacities beyond the pharmaceutical sector alone—an essential consideration for LMICs navigating complex political and economic constraints.
Country Selection Criteria
Four countries—Brazil, Cuba, India, and Iran—were selected for comparative analysis based on the following criteria: (1) LMIC classification by the World Bank; (2) geographic and geopolitical diversity, representing Latin America, South Asia, and the Middle East; (3) active national vaccine development initiatives during the COVID-19 pandemic, including domestic R&D, production, and regulatory oversight; (4) variation in innovation governance models, including state-centric (e.g., Cuba, Iran), hybrid (e.g., India), and public–private arrangements (e.g., Brazil).
This sampling strategy enables balanced assessment of diverse policy and innovation ecosystems in LMICs. It also provides insight into how different institutional configurations and resource constraints influence trajectories toward vaccine sovereignty in lower-resource settings.
Comparative Data Synthesis
A structured matrix was developed to compare national vaccine strategies across 6 dimensions: institutional leadership, platform type, technology transfer, IP ownership, regulatory adaptation, and commercialization models (
Table 1). Visual integration of chronological and institutional dynamics is presented in
Figure 1, which maps vaccine development stages against TRL milestones and associated policy mechanisms. A complementary timeline was also compiled to track country-specific milestones in vaccine development, approval, and deployment (
Table 2).
These tools facilitated cross-case comparison and thematic synthesis by aligning national experiences with innovation and governance benchmarks. Although this is not a systematic review, the literature selection and inclusion process was conducted with a high degree of transparency and rigor. To ensure reproducibility, a PRISMA-style flow diagram is included to summarize the identification, screening, and inclusion process, following PRISMA 2020 principles (
Figure S1) [
15].
Results
The following sections present the key comparative findings across the 4 country cases, beginning with innovation policy frameworks and continuing through implementation and geopolitical dimensions.
Policy Frameworks for Vaccine Innovation
A country’s capacity to respond rapidly to public health emergencies depends not only on scientific capability but also on coherent innovation policies, mission-driven governance, and strategic procurement frameworks that guide both research and deployment.
NISs and vaccine development
The NIS model posits that innovation arises through interactions among public institutions, industry, academia, and regulatory agencies rather than in isolation [
10,
11]. During the COVID-19 pandemic, countries that had already integrated biotechnology into national innovation strategies—such as India and Cuba—were better able to mobilize institutional networks to support vaccine development [
16,
17].
Cuba’s BioCubaFarma and India’s Department of Biotechnology coordinated vaccine development through mission-oriented initiatives that linked scientific R&D with targeted policy incentives. Brazil’s NIS, although institutionally mature, was hindered by bureaucratic bottlenecks and uneven public–private alignment, slowing the adoption of new technologies [
18]. Iran, operating under international sanctions, relied on a centralized model driven by public research institutions and quasi-private biotech firms to preserve vaccine autonomy [
19,
20].
Public-private partnerships and strategic procurement
Public–private partnerships emerged as decisive enablers of vaccine development in all 4 countries. India’s Serum Institute scaled up manufacturing through advance purchase agreements with the Indian government and international organizations such as Gavi [
21]. Brazil’s Fiocruz and Butantan Institute secured international technology transfers but faced delays from procedural and logistical challenges [
22].
Cuba maintained a vertically integrated state model, in which BioCubaFarma managed R&D, production, and procurement—ensuring close coordination between science and policy [
23]. Iran’s strategy incorporated private-sector engagement through firms such as Shifa Pharmed (COVIran Barekat) and CinnaGen (SpikoGen), supported by regulatory fast-tracking under emergency authorization frameworks [
24,
25].
Technology Management Challenges
Managing vaccine R&D during a pandemic requires overcoming specific technical and institutional barriers that extend from early-stage formulation to mass production. These challenges are amplified in LMICs with limited infrastructure or fragile supply chains.
Scientific and technical barriers
High-stakes vaccine development demands expertise in multiple domains, including antigen design, adjuvant formulation, cold chain stability, and quality control systems. Without access to mRNA platforms or proprietary technologies, Cuba and Iran turned to protein subunit and conjugate vaccines, drawing on existing recombinant biotechnology capacities [
26,
27].
India’s Covaxin project, developed by Bharat Biotech in collaboration with the Indian Council of Medical Research (ICMR), faced significant scrutiny during phase II/III trials but advanced through agile iteration and extensive data-sharing partnerships [
28]. Brazil’s Butantan Institute, however, struggled with formulation bottlenecks and fill-and-finish limitations, which complicated scale-up of CoronaVac production [
29].
Regulatory and clinical trials management
Regulatory flexibility was a critical differentiator. India and Iran implemented adaptive licensing mechanisms and rolling reviews to accelerate clinical trials while maintaining safety standards [
21,
27,
28]. Brazil’s multilayered ethics and regulatory procedures, although rigorous, introduced delays in trial approval [
30]. In contrast, Cuba benefited from centralized oversight by national health institutes, which facilitated rapid recruitment and trial progression [
31].
Prototyping and the TRL perspective
In LMIC settings, TRL stages often overlap due to the urgency of vaccine development under resource constraints. For instance, India and Iran progressed to TRL 7 (clinical-grade manufacturing) while still conducting TRL 5–6 clinical trials, reflecting adaptive regulatory practices. Feedback from downstream processes, such as manufacturing scalability and distribution logistics, frequently informed upstream refinements, including dosage adjustments and delivery optimization.
Iran’s SpikoGen and COVOPars vaccines were developed in collaboration with Tehran University of Medical Sciences and the Razi Institute, respectively. These partnerships accelerated the transition from prototype to industrial scale by utilizing established bioreactor systems and GMP-certified facilities [
32,
33]. India’s vaccine pipeline advanced quickly through strong linkages between private manufacturers and international clinical trial networks [
34]. In contrast, Brazil’s ButanVac initiative faced design and regulatory hurdles in early development, exemplifying TRL bottlenecks in contexts where innovation and regulatory ecosystems were misaligned.
These cases illustrate how institutional experience, infrastructure readiness, and adaptive regulation are essential for navigating TRL transitions in resource-constrained environments—elements conceptually mapped in
Figure 1.
Global Coordination, South–South Collaboration, and Public Health Outcomes
The drive for vaccine self-sufficiency in LMICs during the COVID-19 pandemic intersected with global initiatives promoting equitable access, collaborative development, and regional capacity-building. While NISs shaped domestic responses, global mechanisms, such as the WHO C-TAP, the mRNA Technology Transfer Hub in South Africa, and broader South–South collaboration frameworks, provided important benchmarks and opportunities for countries facing structural constraints [
35–
37].
The WHO mRNA Hub, launched with Afrigen Biologics and the Medicines Patent Pool, aimed to disseminate mRNA technologies to LMICs, including Brazil and India, by providing platform training and regulatory support [
35]. Although none of the vaccines studied here directly used mRNA technology from the hub, the initiative exemplifies horizontal collaboration and technology democratization. Similar principles were visible in co-development ventures such as the PastoCovac alliance between Cuba’s Finlay Institute and Iran’s Pasteur Institute [
38]. These partnerships highlighted deeper South–South knowledge exchange beyond licensing—emphasizing joint R&D, distributed manufacturing, and regulatory co-approval.
Brazil and India also leveraged their positions in global vaccine manufacturing to expand bilateral and multilateral knowledge-sharing. India’s Vaccine Maitri program exported more than 66 million doses of domestically produced vaccines to over 90 countries during the pandemic, reflecting not only large-scale industrial capacity but also the strategic use of soft power and regional diplomacy [
39]. Brazil’s Butantan Institute, although constrained in its attempt to indigenize ButanVac, continued to operate as a WHO-designated National Regulatory Authority and served as a training hub for regional vaccine developers, including collaborations within the Pan American Health Organization (PAHO) framework [
40].
From a public health perspective, these innovation trajectories produced significant yet variable outcomes. Iran achieved rapid emergency use authorization for multiple domestic vaccines by mid-2021, vaccinating a substantial proportion of its population despite international sanctions [
41]. India’s dual-track strategy simultaneously pursuing domestic mass vaccination and global engagement positioned it as both a manufacturing hub and a diplomatic actor during the pandemic, underscoring the strategic value of combining innovation with global health solidarity [
42]. Cuba, through strong state-led coordination, vaccinated more than 90% of its population with homegrown vaccines (Soberana and Abdala) by early 2022, achieving one of the highest global coverage rates [
43]. These cases illustrate how institutional preparedness, global engagement, and adaptive capacity shaped LMIC vaccine ecosystems.
Despite uneven access to global IP and platform technologies, the pandemic demonstrated that LMICs could align with or replicate multilateral initiatives to build domestic capacities. South–South cooperation, underpinned by aligned governance structures and shared scientific missions, emerged as a pragmatic strategy to reduce dependency on Northern suppliers. These experiences highlight the strategic importance of shared innovation platforms for advancing health sovereignty, particularly in contexts where access to global supply chains remains constrained.
Geopolitical pressures, including sanctions, IP restrictions, and limited access to multilateral funding, further shaped innovation pathways. In particular, Iran and Cuba adapted to these barriers by fostering indigenous solutions and forging South–South alliances. These cases highlight how geopolitical constraints can serve both as obstacles and as drivers, pushing LMICs toward more autonomous vaccine development strategies with long-term implications for future pandemic preparedness.
Commercialization Pathways and Strategic Scaling
Translating vaccine candidates into widely distributed products requires strategic commercialization mechanisms, including licensing agreements, IP management, contract manufacturing, and regulatory harmonization. For LMICs, these processes must also contend with systemic barriers such as supply chain limitations, market access challenges, and geopolitical pressures.
Technology transfer and licensing
India and Brazil pursued international partnerships to acquire technological expertise. The Serum Institute of India secured non-exclusive licenses from AstraZeneca and Novavax to manufacture Covishield and Covovax, respectively [
44]. Brazil’s Fiocruz entered a technology transfer agreement with AstraZeneca to locally produce Vaxzevria. However, delays in process transfer and scale-up generated late-stage production bottlenecks [
45].
In contrast, Cuba and Iran—confronted with geopolitical restrictions and IP barriers—relied largely on indigenous platforms. Development and internal commercialization of Cuba’s Soberana and Abdala vaccines were supported through centralized IP governance under BioCubaFarma [
46]. Iran’s Pasteur Institute co-developed Soberana-02 with Cuba, while COVIran Barekat, SpikoGen, and COVOPars were advanced by domestic biopharmaceutical firms managing their own IP portfolios [
47–
49].
While bilateral licensing arrangements accelerated vaccine output in India and Brazil, they frequently depended on proprietary platforms that limited local control over upstream technologies such as cell lines and adjuvants. This dependency raises concerns about long-term self-reliance, particularly when IP restrictions constrain access to updated variants or platform know-how.
Supply chain and manufacturing scale-up
Scaling vaccine production requires reliable access to active pharmaceutical ingredients (APIs), fill-and-finish facilities, cold chain logistics, and robust quality assurance systems. In India, Covaxin production was supported by a consortium including Bharat Biotech and Indian Immunologicals Ltd., underpinned by the government’s Mission COVID-19 Suraksha [
50]. Brazil, however, experienced delays in its early rollout due to reliance on imported APIs [
51].
Iran addressed supply constraints by expanding biosafety-level-2 facilities and scaling bioreactor capacity through firms such as Shifa Pharmed and CinnaGen [
52]. Cuba mitigated cold chain challenges by deploying thermostable formulations and lyophilized products, facilitating smoother domestic distribution [
53].
Despite these achievements, the sustainability of large-scale production remains uncertain in the post-pandemic era. Brazil and India face fiscal pressures in maintaining manufacturing capacity without sustained global procurement, while Iran and Cuba continue to depend on strong state support for operational and regulatory continuity. Achieving long-term vaccine sovereignty in LMICs will require not only innovation but also durable industrial financing.
Comparative Case Studies: Brazil, Cuba, India, and Iran
To contextualize the interplay between innovation and policy in vaccine development, a comparative analysis was undertaken across 4 countries representing diverse governance models, industrial maturity, and geopolitical conditions (
Table 1) [
9,
17,
21,
23,
25,
27,
32,
46–
53].
The analysis shows that countries with centralized governance and vertically integrated biotech sectors—such as Cuba and Iran—were more successful in retaining local ownership of R&D and ensuring end-to-end commercialization. India’s hybrid public–private model enabled rapid international collaboration and licensing, while Brazil’s dependence on foreign IP and procedural inefficiencies limited early scalability. Regulatory agility, institutional alignment, and domestic production autonomy emerged as central enablers of timely vaccine rollout [
54].
Table 2 maps vaccine R&D milestones, partnerships, and licensing decisions across 2020–2022, highlighting temporal patterns of innovation, collaboration, and deployment.
Cuba and Iran initiated indigenous vaccine projects as early as mid-2020, while India and Brazil initially relied on technology access from external sources. This progression underscores not only technical timelines but also the policy choices that determined when and how countries launched mass vaccination programs. It further highlights the strategic role of pre-existing biotech ecosystems in enabling rapid and autonomous responses.
Building on this chronological overview,
Table 3 provides a comparative analysis of the organizational structures, R&D models, and primary challenges encountered by Brazil, Cuba, India, and Iran in their COVID-19 vaccine development efforts.
This comparative lens highlights the diverse approaches and constraints each country faced, shaped by distinct political, economic, and infrastructural contexts. Understanding these factors offers deeper insight into the structural complexity of global vaccine development and distribution.
The impact of these innovation strategies is evident in national outcomes. By late 2021, India had exported more than 66 million doses of Covishield to over 90 countries under COVAX and bilateral agreements. Cuba vaccinated over 90% of its population with domestically developed vaccines and supplied doses to Venezuela, Nicaragua, and Vietnam. Iran achieved full-cycle production capacity for at least 3 vaccine types despite the burden of international sanctions. Brazil, through Fiocruz, scaled fill-and-finish capacity to produce more than 100 million doses of AstraZeneca’s vaccine. Collectively, these achievements underscore how the integration of innovation and policy directly shaped real-world access, resilience, and autonomy [
27,
46,
55].
Geopolitical barriers—particularly the United States-led sanctions on Iran and Cuba—posed major obstacles to technology transfer, raw material imports, and participation in multilateral procurement mechanisms such as COVAX. Despite these challenges, both countries advanced public-sector-driven vaccine R&D. Nevertheless, limited access to international IP and funding mechanisms restricted their ability to scale production. The long-term sustainability of such domestically centered programs remains uncertain, particularly in the absence of integration into global supply chains or reliable financing beyond the emergency phase.
Discussion
The preceding results highlight the diverse institutional models, innovation pathways, and commercialization strategies adopted by Brazil, Cuba, India, and Iran. In this section, these case-specific insights are considered collectively to identify broader patterns in vaccine development within LMICs. The discussion emphasizes shared challenges, enabling factors, and implications for both national and international health policy, followed by actionable recommendations for strengthening vaccine innovation ecosystems in resource-constrained contexts.
Broader Findings and Thematic Insights
Across the 4 case studies, several cross-cutting themes emerge that provide lessons for policymakers and vaccine developers. While sector-specific factors, such as regulatory design and manufacturing pathways, were important, the broader institutional and governance context, framed by the NIS approach, was equally critical in shaping vaccine outcomes: (1) Strategic sovereignty in health technologies: Countries with prior investments in state-led bioscience and pharmaceutical sectors, notably Cuba and Iran, achieved vaccine autonomy despite geopolitical restrictions. Control over IP and production facilities was pivotal in ensuring independence; (2) Maturity of innovation ecosystems: India successfully leveraged both public and private sector strengths, combining in-house R&D with licensed foreign IP. By contrast, Brazil—despite its strong scientific capacity—was constrained by fragmented governance and weak institutional coordination; (3) Regulatory co-evolution: Adaptive regulatory mechanisms, such as India’s Emergency Use Authorization and Iran’s conditional approval processes, expedited vaccine rollout while upholding safety standards. Brazil’s more rigid, multilayered ethics clearance processes introduced delays; (4) South-south scientific collaboration: The Iran–Cuba co-development of PastoCovac illustrates how Global South partnerships can overcome access barriers, facilitating shared technology platforms and joint clinical trials; (5) Distributed manufacturing models: Countries that mobilized both state and private sector manufacturers, particularly India and Iran, demonstrated greater resilience to supply chain shocks and achieved more flexible production scale-up.
Policy Implications and Recommendations
Drawing from the comparative analysis, this section outlines key policy recommendations for LMICs seeking to strengthen their vaccine innovation systems:
Institutional capacity and public R&D support
National innovation strategies should prioritize consistent financing for public research institutions and long-term workforce development. Evidence from Cuba and Iran confirms that such investments generate resilience during crises.
Strategic IP management
Balancing local innovation with licensed production is essential. India’s hybrid approach—blending domestic R&D with foreign IP—offers a model for enhancing sovereignty while maintaining global integration.
Regulatory preparedness
Developing fast-track, adaptable regulatory pathways in advance of emergencies is crucial. Institutionalizing foresight practices within regulatory systems can ensure timely approvals during future crises.
Regional vaccine hubs and south-south alliances
Cross-border collaboration among LMICs in vaccine R&D, clinical trials, and API production—exemplified by the Cuba–Iran alliance—can foster collective self-sufficiency and diversify global vaccine sources. These national experiences also resonate with WHO-led mechanisms such as the C-TAP and the mRNA Technology Transfer Hub in South Africa. The Iran–Cuba collaboration on PastoCovac, along with India’s vaccine diplomacy through Covishield exports, reflects shared objectives of equitable technology exchange and distributed manufacturing. Strengthening such South–South collaborations could provide parallel or complementary pathways to WHO’s multilateral platforms in addressing inequitable vaccine access during future pandemics [
56,
57].
Open access to technology
LMICs should actively engage in initiatives such as the WHO C-TAP to encourage equitable knowledge-sharing and reduce dependence on restrictive IP regimes.
Implications for multilateral health governance
The vaccine innovation and policy trajectories of Brazil, Cuba, India, and Iran carry significant implications for multilateral pandemic preparedness. Their experiences underscore the importance of flexible IP frameworks, diversified manufacturing, and public–private integration—factors that could guide reforms to COVAX governance, WHO Pandemic Accord negotiations, and regional regulatory harmonization efforts [
58]. For example, decentralized innovation models in India and Iran align with the African Union and Association of Southeast Asian Nations calls for local manufacturing ecosystems [
59]. Similarly, Cuba’s and Iran’s reliance on self-developed platforms underscores the necessity of national R&D investment in contexts where geopolitical barriers restrict access to multilateral resources.
To strengthen LMIC vaccine sovereignty, international organizations such as WHO can play a catalytic role by building pooled R&D platforms, pre-negotiating IP licenses during non-crisis periods, and ensuring equitable access to critical inputs. Initiatives such as the WHO mRNA Technology Transfer Hub and C-TAP should be reinforced with dedicated financing, sustained political support, and regional implementation mechanisms to ensure LMIC participation is substantive rather than symbolic. A WHO-led coordination framework could further enhance resilience by supporting regulatory alignment, pooled raw material procurement, and global clinical trial data-sharing.
Synthesis for LMIC policy pathways
Collectively, the cases of Brazil, Cuba, India, and Iran demonstrate that LMICs can pursue diverse yet effective innovation trajectories when public health goals are embedded in broader science and technology strategies. While no single model applies universally, transferable lessons include the strategic value of sustained investment in public research capacity, the establishment of adaptable regulatory systems, and the strengthening of South–South knowledge networks. LMICs can also leverage global platforms such as the WHO mRNA Hub and C-TAP without undermining national sovereignty, particularly when aligned with regional regulatory harmonization initiatives (e.g., through the African Medicines Agency or PAHO). Ultimately, equitable vaccine access depends not only on technology availability but also on reinforcing LMIC agency in governance, manufacturing, and innovation leadership.
In addition, the long-term economic sustainability of domestic vaccine programs remains a critical issue, particularly for LMICs confronting fiscal constraints in the post-emergency phase. Institutional frameworks must also anticipate barriers posed by sanctions and trade restrictions, which limit technology access and R&D financing.
