Exploring the potential of mRNA vaccines in combatting communicable and non-communicable diseases in low-income and lower-middle-income countries

Abstract

The global health landscape is increasingly dominated by a double burden of communicable diseases (CDs) and non-communicable diseases (NCDs), with low-income and lower-middle-income countries (LMICs) being disproportionately affected due to geographic, demographic, and socioeconomic vulnerabilities. While infectious diseases like HIV/AIDS, tuberculosis, malaria, and diarrheal illnesses continue to cause high mortality rates, particularly in LMICs, NCDs such as cardiovascular disease, cancer, diabetes, and chronic pulmonary conditions are rising rapidly due to demographic shifts and lifestyle changes. This dual burden not only contributes to high morbidity and mortality but also results in significant economic losses due to treatment costs and reduced productivity. World Health Organization projections suggest that by 2050, NCDs will account for 70% of all deaths in LMICs. This study aimed to explore recent literature on the impact of communicable diseases and NCDs in these regions and assess the potential role of mRNA vaccine technology in addressing this growing crisis. The findings indicate that mRNA vaccines have emerged as a transformative innovation in the field of vaccinology, offering rapid, adaptable platforms for addressing both infectious diseases and virus-induced cancers. The study highlights that mRNA vaccines could play a pivotal role in personalized and efficient disease management. However, barriers such as vaccine stability, cold-chain storage requirements, and delivery logistics hinder their implementation in resource-limited settings. This study emphasizes the need for targeted strategies to overcome these challenges and extend the benefits of mRNA vaccines to developing nations.

Introduction

Low-income and lower-middle-income countries (LMICs) have been increasingly burdened by both communicable and non-communicable diseases. The disease landscape includes a wide range of conditions such as cardiovascular diseases, diabetes, cancer, chronic respiratory illnesses, mental health disorders, and infectious diseases like HIV/AIDS, malaria, and tuberculosis (TB)^[1^]. Additionally, these countries are dealing with outbreaks of both emerging and re-emerging diseases such as measles, hepatitis, cholera, meningitis, and Ebola^[2^]. Malaria, HIV/AIDS, and TB are among the most prevalent and deadly, contributing to high morbidity, mortality, and socioeconomic disruption. These diseases disproportionately affect LMICs, where healthcare infrastructure is often inadequate^[3^].

HIGHLIGHTS

• Dual disease burden and the role of mRNA vaccines in developing nations.

• Addressing communicable diseases and non-communicable diseases with mRNA Technology.

• Innovative vaccine approaches for global health equity.

• Key barriers to mRNA vaccine implementation.

• Tackling global health challenges with mRNA vaccines.

Malaria remains a critical public health issue, particularly in sub-Saharan Africa. Approximately 95% of deaths occur in the African Region, where many at-risk people still lack access to the services they need to prevent, detect, and treat the disease. Although interventions like insecticide-treated bed nets and antimalarial medications have helped reduce the burden of malaria, the disease still poses a serious threat, especially in areas with limited healthcare access. Ongoing challenges such as drug resistance, mosquito adaptation, and, critically, the lack of a widely available and effective vaccine make malaria difficult to eliminate^[4^]. For malaria, mRNA vaccines are being explored to target the Plasmodium parasite, which causes the disease. Researchers aim to use mRNA to induce an immune response that can prevent infection or reduce malaria severity. Early-stage trials have shown promise, though more research is needed^[5^].

HIV/AIDS continues to impact millions of lives, especially in Sub-Saharan Africa, which accounts for nearly 70% of the world’s HIV cases, where the virus weakens the immune system and makes people more vulnerable to other infections and cancers^[6^]. While antiretroviral therapy (ART) has brought hope by improving the quality of life for many, access to treatment remains unequal, and stigma still prevents many from seeking help or staying on medication^[7^]. For HIV, mRNA vaccines could elicit strong, broad immune responses to the virus, addressing challenges such as viral mutation and immune evasion^[8^]. There is no widely available vaccine. While several candidates are in development, the virus’s high mutation rate and ability to evade the immune system have made creating an effective vaccine difficult^[9^].

TB, one of the oldest known human diseases, remains the deadliest infectious disease worldwide, even with the global use of a live attenuated vaccine and multiple antibiotics^[10^]. Many LMICs still struggle with it, as it remains a major health concern. The Bacillus Calmette–Guérin (BCG) vaccine, first introduced over a century ago, is still the only approved vaccine for TB. While it helps protect young children from the most severe forms of TB, such as TB meningitis, it is far less effective at preventing pulmonary TB, the most common and contagious form that affects adults and drives the most transmission. This limitation is particularly concerning in high-burden regions, where the vaccine’s protection often fades with age and may be reduced by environmental factors^[11^]. Recognizing this gap, researchers and global health organizations are actively working on developing new, more effective TB vaccines. Promising candidates, such as M72/AS01E, have shown encouraging results but still face challenges in terms of safety, long-term protection, and large-scale production^[12^]. Despite decades of use, BCG’s shortcomings highlight the urgent need for continued innovation and investment in better TB vaccination strategies to protect people of all ages and truly move toward TB elimination.

Current vaccination strategies for malaria, HIV, and TB have made significant progress, but challenges remain in their effectiveness and accessibility. For malaria, the RTS,S/AS01 (Mosquirix) vaccine is the first to be approved for use, showing modest efficacy in preventing malaria in young children. However, its effectiveness wanes over time, and it does not provide complete protection. Efforts are ongoing to develop more effective malaria vaccines, but challenges include the complex life cycle of the parasite and the development of resistance^[13^]. mRNA technology holds promise for the treatment of TB and HIV. For TB, mRNA vaccines could enhance the immune response against the bacterium Mycobacterium TB. While still in the experimental phase, mRNA vaccines offer exciting new possibilities for preventing malaria, TB, and HIV, potentially revolutionizing the fight against these diseases^[14^]. Although advances have been made in disease management and prevention, significant gaps persist in vaccine accessibility and efficacy. Emerging vaccine technologies, particularly those utilizing mRNA platforms, offer new hope for disease control and eventual eradication. mRNA vaccines can be developed much faster than traditional vaccines, making them ideal for rapid response to health crises and supporting wider global access^[15^].

According to global statistics, cancer is also one of the most prominent public health and socioeconomic challenges of the 21st century^[16^]. Over the past several decades, the incidence and mortality of cancer have risen sharply in LMICs. Due to the lack of early screening programs, preventive measures, affordable treatment options, and well-developed oncology infrastructure, patients in LMICs are often diagnosed at advanced stages of disease, resulting in persistently high mortality rates^[17^]. In addition, some cancers remain disproportionately prevalent in LMICs. For example, cervical cancer continues to be one of the most common malignancies among women in LMICs, whereas its incidence has declined markedly in high-income countries^[18^]. Therefore, the development of effective and affordable approaches for prevention, diagnosis, and treatment is particularly critical for cancer control.

This review aims to explore the potential and challenges of mRNA vaccines for non-communicable and communicable diseases. By examining recent advancements, ongoing research, and the hurdles that remain, this review seeks to provide a comprehensive understanding of how mRNA technology could transform the landscape of communicable and non-communicable diseases in LMICs and to assess the potential role of mRNA vaccine technology in addressing this growing crisis, particularly in resource-limited settings.

Understanding mRNA vaccine technology

Background and principle of mRNA vaccines

A vaccine is a biological preparation derived from living organisms that trains the immune system to recognize specific antigens and provides long-term protection without causing illness^[19^]. Traditional platforms such as live-attenuated, inactivated, protein subunit, and viral vector vaccines have been used and have successfully controlled infectious diseases such as smallpox and polio^[20^]. However, they are limited by safety concerns, complex manufacturing processes, and lengthy development timelines. These challenges are particularly critical for emerging threats such as Ebola virus disease and Marburg virus disease in LMICs.

Vaccine distribution faces significant challenges primarily due to the strict storage requirements necessary to maintain vaccine efficacy. Most vaccines require a continuous cold chain, where they are stored and transported within precise temperature ranges. Any deviations can compromise their potency. Maintaining this cold chain is complex, involving multiple stages from production to delivery, and becomes particularly critical during outbreak situations where rapid vaccination is essential. Inadequate cold storage facilities, unreliable electricity, and outdated infrastructure, especially in LMICs, increase the risk of vaccine spoilage and reduce overall immunization effectiveness^[21,22^].

Transportation logistics further complicate vaccine distribution. Specialized vehicles with temperature-controlled compartments are often required, and remote or hard-to-reach areas may experience delays due to poor road networks and geographical barriers. These issues are exacerbated during health emergencies, as delays in vaccine delivery can hinder disease containment. Improving transportation systems, investing in reliable vehicles, and employing innovative solutions, such as drone deliveries or mobile clinics, are strategies to address these logistical hurdles, ensuring vaccines reach all communities in a timely manner^[23,24^].

Coordination and supply chain visibility are also critical challenges. Efficient distribution requires real-time monitoring of vaccine shipments, inventory, and temperature conditions. Gaps in communication, lack of robust tracking systems, and limited collaboration among manufacturers, distributors, and healthcare providers can lead to inefficiencies, wastage, and inequitable access. Addressing these gaps involves deploying modern technologies such as temperature sensors, data loggers, and digital tracking systems to enhance transparency and responsiveness throughout the supply chain^[25^].

Vaccine development employs diverse strategies, each with distinct advantages and challenges. Conjugate vaccines enhance immunity by linking weak antigens to strong carrier proteins, while live vaccines elicit robust immune responses but carry risks for immunocompromised individuals. Non-live vaccines are safer but may require multiple doses or adjuvants, and genomics-based vaccines use genome analysis to identify novel antigens for hard-to-culture pathogens. Advanced delivery systems such as microspheres and liposomes further improve antigen presentation and immune activation, reflecting the evolving multi-dimensional approaches in modern vaccine design^[26,27^]. Emerging vaccine technologies and alternative storage solutions offer potential remedies but bring new complexities.

A few years ago, the COVID-19 pandemic catalyzed the rapid development of messenger RNA (mRNA) vaccine technology, with Pfizer-BioNTech and Moderna leading the way in producing vaccines that demonstrated remarkable effectiveness and a good safety profile, with a significant global health impact^[28^]. The success of COVID-19 vaccines has firmly established mRNA as a flexible and powerful therapeutic platform. Its growing clinical applications now extend beyond infectious diseases to include cancer immunotherapies targeting oncogenes and tumor suppressor genes, as well as treatments for autoimmune disorders and a range of non-immunotherapeutic uses^[29^].

mRNA vaccines comprise synthetic mRNA molecules that direct the production of antigen-specific proteins and induce an immune response. Particularly, the success of mRNA vaccines against the SARS-CoV-2 pandemic was built on decades of research that enabled the optimization of mRNA constructs^[30^]. mRNA vaccines include non-replicating mRNA (nrRNA) vaccines, such as those used against COVID-19, which deliver antigen-encoding RNA that is directly translated without self-replication; self-amplifying RNA (saRNA) vaccines, which include replicase machinery that enables intracellular RNA amplification, thereby inducing stronger immune responses at lower doses; trans-amplifying RNA (taRNA) vaccines, which separate the replicase and antigen into two distinct RNAs, offering greater modularity and improved safety; and circular RNA vaccines, which form closed-loop structures that enhance stability and prolong antigen expression^[31^].

mRNA vaccine design and mechanism of action of mRNA vaccine

The process of mRNA vaccine development starts with the design and optimization of mRNA, which involves multiple structural and sequence modifications to enhance stability, translation efficiency, and safety^[32^]. The critical features are: designing mRNA in 5′ to 3′ direction, 5′ end protection by capping through incorporating a 7-methylguanosine linked via a triphosphate bridge and 2′-O-methylation of adjacent nucleotides to prevent recognition by innate immune sensors and protects against exonuclease degradation, the 3’polyadenylation typically with over 100 nucleotides long, that works synergistically with the 5′ cap in binding proteins to stabilize the transcript and regulate translation, engineering sequences to minimize chance of RNA strand degradation and enhance ribosome recruitment through 5′ and 3′ untranslated regions (UTRs)^[28^]. Finally, optimize the open reading frame, considering the start codon (AUG) and stop codons (UAA, UAG, or UGA), to increase translation without altering the protein product or its modifications^[31^].

Additionally, incorporating modified nucleosides such as pseudouridine or N1-methylpseudouridine helps evade pattern-recognition receptors, thereby preventing unwanted immune activation and allowing robust protein expression, as used in the Pfizer-BioNTech and Moderna vaccines^[33^]. For mRNA vaccines to exert their intended effect, the nucleic acid encoding a specific viral or bacterial antigen must be efficiently delivered. To achieve this, the in vitro transcribed mRNA is encapsulated in delivery vehicles such as lipid nanoparticles (LNPs), lipoplexes, or proteolipids, which protect the mRNA from degradation and facilitate its uptake by antigen-presenting cells^[30^]. Figure 1 illustrates the structural design considerations for mRNA vaccine optimization.

Figure 1.

mRNA design optimization^[30^].

When administered, mRNA vaccines are taken up by antigen-presenting cells (APCs) through endocytosis. Once inside the cell, the mRNA is released from the endosome into the cytoplasm, where it is translated by ribosomes into the encoded antigenic protein^[34^]. Intracellular antigens translated from mRNA are degraded by the proteasome and presented on MHC class I molecules to cytotoxic T cells, which eliminate infected cells through perforin- and granzyme-mediated pathways^[28^]. In parallel, secreted or extracellular antigens can be taken up by APCs, processed in endosomes, and displayed on MHC class II molecules to helper T cells. Activated helper T cells modulate immunity by stimulating B cells to produce neutralizing antibodies and by releasing cytokines that activate phagocytes, such as macrophages^[31^]. This coordinated activation of both cellular and humoral immunity effectively mimics natural infection, yet without the presence of live pathogens, as shown in Figure 2.

Figure 2.

Mechanism of action of mRNA vaccines in inducing immune responses^[34^].

Artificial intelligence in mRNA vaccine design to combat communicable and non-communicable diseases

The global landscape of mRNA innovation is advancing at remarkable speed, propelled not only by breakthroughs in molecular biology but also by the growing integration of artificial intelligence (AI)^[35^]. The integration of AI into vaccine development has revolutionized traditional methodologies, significantly enhancing the speed, precision, and scalability of immunological research. Emerging and re-emerging infectious diseases, driven by zoonotic spillovers, antimicrobial resistance (AMR), and global environmental changes, pose substantial challenges^[36,37^]. Addressing these requires innovative approaches, with AI playing a pivotal role in advancing immunological solutions. A notable example is BioNTech’s creation of an AI research hub in the UK, highlighting how computational capabilities are becoming integral to the development of next-generation mRNA therapeutics. As the field shifts from largely empirical experimentation to data-driven design strategies, AI offers transformative opportunities to accelerate and standardize progress throughout the entire development pipeline^[38,39^]. Through predictive modeling, multi-omics integration, and automated design cycles, AI-driven approaches help overcome persistent challenges related to stability, safety, and efficacy that have historically limited clinical translation. This review explores how AI-guided strategies are redefining mRNA therapeutics from antigen identification and sequence optimization to LNP formulation and safety evaluation, establishing AI as a key force in advancing precision medicine in the mRNA era^[40^].

mRNA vaccines stimulate immune responses by encoding disease-specific antigens, making the identification of accurate and effective targets a fundamental step in their design. Historically, cancer immunotherapy has focused on tumor-associated antigens that are overexpressed in malignant tissues. However, because these antigens may undergo thymic negative selection, they can induce central immune tolerance and potentially increase the risk of autoimmune reactions^[41^].

More recently, research has shifted toward tumor-specific antigens (TSAs), also known as neoantigens, which primarily arise from genetic alterations within cancer cells. Unlike tumor-associated antigens, TSAs are uniquely expressed in tumor tissue and absent from normal cells, allowing them to bypass central immune tolerance. As a result, neoantigens are less likely to provoke autoimmunity and are more capable of generating strong, tumor-selective immune responses, making them highly attractive targets for personalized mRNA vaccine strategies^[42,43^].

Neoantigens emerge from molecular changes across multiple biological layers. At the genomic level, they originate from somatic mutations such as single-nucleotide variants, insertions and deletions, gene fusions, microsatellite instability, and structural rearrangements. At the transcriptomic level, they can result from alternative splicing, alternative polyadenylation, RNA editing, and peptides derived from non-coding RNAs. Proteomic alterations, including abnormal translation processes and post-translational modifications, also contribute to the production of immunogenic peptides. AI is transforming critical domains, including multi-omics–driven neoantigen identification, optimization of coding sequences and UTRs, rational design of LNPs, and in vivo pharmacological forecasting^[44^]. Together, the integration of AI with next-generation mRNA technologies is opening the path toward a new era of clinically actionable, precision-guided mRNA therapeutics.

Limitations and challenges of mRNA vaccines

Despite their clear advantages, mRNA vaccines face significant challenges, particularly in LMICs, where limitations in manufacturing capacity, infrastructure, and cold-chain systems remain critical barriers^[45^]. Although the in vitro transcription process is conceptually simple, mRNA vaccines require advanced technology and are more thermosensitive than conventional vaccines, complicating storage, distribution, and delivery and increasing the risk of wastage^[46^]. Producing clinical-grade mRNA vaccines requires substantial resources and facilities, including GMP-compliant manufacturing plants, reliable cold-chain systems, highly skilled personnel, robust regulatory frameworks, and coherent policies^[47^]. These requirements present considerable obstacles in LMICs, where resources are often scarce. Furthermore, vaccine hesitancy caused by misinformation and weak policies can limit uptake^[48^]. Without strategic policies, sustainable funding, public and private investments, technology transfer, advanced research and development (R&D), infrastructure development, intercontinental collaboration, regulatory strengthening, and community engagement, the transformative potential of mRNA vaccines in LMICs will be constrained.

mRNA vaccines for malaria treatment

Overview of malaria burden and progress with malaria mRNA vaccines

Malaria remains a major public health challenge in sub-Saharan Africa, with Plasmodium falciparum accounting for approximately 98% of cases^[49^]. Control and preventive measures have been implemented^[50^], and the introduction of vaccines, including RTS,S and R21, in selected countries has contributed to reductions in malaria incidence, collectively playing a significant role in decreasing the burden of disease^[51^]. Despite these advancements, malaria persists as a major global health issue, with a concerning resurgence noted in recent years^[52^]. To date, artemisinin-based combination therapies (ACTs) remain the cornerstone of malaria treatment and have demonstrated high efficacy across many endemic regions^[53^]. However, molecular surveillance has identified specific genetic markers strongly associated with ACT drug resistance^[54^]. In response to these challenges, vaccines such as RTS,S and R21 circumsporozoite protein (CSP)-targeting vaccines have been introduced, but their efficacy has been limited^[55^]. These limitations are partly due to their focus on a single antigen, CSP, as well as the high antigenic diversity and polymorphism of Plasmodium falciparum. This underscores the need for more effective vaccine strategies. mRNA-based vaccines, capable of encoding multiple antigens, offer a promising approach to overcoming the challenges posed by malaria’s disease burden, drug resistance, and the shortcomings of current vaccine options.

The development of mRNA vaccines for malaria has gained momentum following the global rollout of SARS-CoV-2 (mRNA-LNP) vaccines, which demonstrated both efficacy and scalability^[56^]. The limitations of RTS,S, with 36% efficacy in children, highlight the need for more potent next-generation vaccines to meet the World Health Organization goal of ≥75% efficacy by 2030^[57^]. These studies have shown that mRNA vaccines encoding Plasmodium falciparum CSP can elicit protective humoral and T-cell responses, though efficacy was initially modest. To enhance immunogenicity, innovative constructs such as MIP3α-CSP mRNA have been developed, targeting immature dendritic cells and yielding significantly stronger CD4+ T-cell and antibody responses in murine models compared to CSP mRNA-LNP alone^[58^]. In parallel, transmission-blocking vaccines (TBVs) are being explored on the mRNA platform to disrupt parasite development in mosquitoes. Constructs encoding sexual-stage antigens, notably Pfs25 and Pfs230D1, have demonstrated robust immunogenicity when engineered with glycosylphosphatidylinositol anchors or transmembrane domains, ensuring high cell-surface antigen display^[5^].

Preclinical and clinical trials of malaria mRNA vaccines, and their challenges in LMICs

Preclinical investigations have established proof-of-concept for malaria mRNA vaccines by demonstrating their capacity to elicit protective immune responses in animal models^[56^]. Among the novel targets, ribosomal protein L6 (RPL6) has gained attention as a conserved and structurally stable antigen with the potential to overcome challenges posed by antigenic variability. In a recent study, Ganley and colleagues reported that an RPL6-based mRNA vaccine induced robust liver-localized cellular immunity and protected 80% of mice challenged with sporozoites^[59^]. This protection was mediated by liver-resident CD8⁺ tissue-resident memory T cells and was critically dependent on the inclusion of the α-galactosylceramide adjuvant to achieve high efficacy.

In contrast, most mRNA malaria vaccine candidates currently in preclinical development have targeted the CSP to induce strong humoral responses, with some formulations also achieving balanced T-cell immunity^[60^]. For instance, PfCSP mRNA-LNP vaccines have conferred sterile protection in subsets of murine models, with efficacy shown to improve through dose optimization and immunization schedules. Furthermore, dendritic cell-targeting constructs such as MIP3α-CSP fusions have demonstrated superior antibody titers and enhanced CD4⁺ T-cell responses compared to conventional CSP-based mRNA vaccines. In parallel, mRNA-based TBVs encoding sexual-stage antigens, notably Pfs25 and Pfs230D1, are being developed to elicit high-titer functional antibodies that inhibit parasite development within the mosquito vector^[58^]. Preclinical studies with mRNA and mRNA-like platforms encoding these antigens have achieved durable transmission-reducing activity, while protein-based conjugates of Pfs25 and Pfs230 have already advanced into early-phase clinical trials, underscoring the feasibility of TBV targets for human application^[5^].

The primary challenge of mRNA vaccines is selecting antigen combinations to address parasite diversity and optimizing adjuvants and delivery systems for tissue-specific immunity^[61^]. The genetic variability of Plasmodium species may compromise vaccine efficacy, which necessitates the development of multivalent formulations capable of providing broader protection across circulating strains. The complexity of the parasite life cycle further compounds this challenge, since different developmental stages express distinct antigens that vary in immunodominance and protective potential^[56^]. Another major limitation is the limited durability of immune responses^[31^]. Another challenge for malaria mRNA vaccines is their deployment in LMICs, where the burden of disease is highest. Unlike RTS,S, which is stable at standard refrigeration, current mRNA- LNP formulations require ultra-cold storage (−20°C to −70°C), conditions that are difficult to maintain in rural endemic areas with limited infrastructure and unreliable electricity^[45^].

mRNA vaccines for HIV treatment

Overview of global burden of HIV in LMICs, and HIV-1 master of immune evasion

HIV/AIDS remains a major global health challenge, with 39.9 million people living with the virus and 630 000 deaths in 2023 alone. Sub-Saharan Africa bears 75% of the global burden, and funding cuts could lead to 2.9 million of the 3 million projected new infections in the region over the next 5 years^[62,63^]. In LMICs, in particular, the disease burden disproportionately affects children, people in same-sex marriages, and sex workers, to name a few, partly because of limited access to HIV diagnosis and ART among these populations^[64^]. However, long-term adherence to ART exacerbates the risk of other comorbidities, notably liver and cardiovascular diseases, especially in elderly patients^[65^], highlighting the urgent need to develop HIV vaccines.

HIV-1, the most common type of human immunodeficiency virus, evades the immune system effectively, primarily through its Env glycoprotein, the main vaccine target responsible for interacting with host cells and triggering immune responses^[66^]. The HIV-1 vaccine conundrum stems from the virus’s ability to generate a plethora of strains, with extraordinary diversity as early as 24 hours after infection^[67,68^]. It is challenging to design a vaccine with the potential to produce broadly neutralizing antibodies against multiple HIV-1 subtypes and strains circulating globally^[69^]. Compounding this is the ability of the Env protein to evade the immune system. First, Env proteins form low-density, tiny spikes, ranging from 7 to 14, on the viral surface, which are not only poor immunogens^[70,71^] but are also camouflaged by a dense layer of glycans that conceal approximately 50% of gp120 proteins, thereby masking antibody-neutralizing epitopes^[72,73^]. Furthermore, the Env proteins undergo temporal conformational changes upon HIV fusion with host cells^[74^], further adding a layer of complexity to make it a reliable target.

Besides, HIV infection diminishes CD4 T cells, which usually play a crucial role in mounting vaccine-mediated immune responses, and evidence from the literature suggests that people living with HIV (PLWH) can activate CD4 T cells and develop antibodies that are impotent in terms of immunity protections, further implicitly mirroring our meager knowledge on nature of CD4 T cell interactions and HIV^[75^]. Moreover, HIV can enter a dormant stage, and infected CD4 T cells remain out of the vaccine and ART reach for many decades, underscoring the array of evasive chicanery at its disposal^[76^].

Interestingly, despite HIV’s ability to diversify its genome, employ structural protections, and manipulate CD4 T cells, some PLWH can develop broadly neutralizing antibodies due to their B-cell precursors, which have undergone intricate processes of somatic hypermutation in germinal centers, thereby empowering them to counteract HIV effectively^[77,78^]. As discussed below, scientists are now taking advantage of modern technology, notably mRNA vaccines, together with other tools like lipid or viral-like nanoparticles, to generate vaccines endowed with the potential to elicit broadly neutralizing antibodies (bnAbs).

A key HIV vaccine strategy involves priming the immune system with an initial immunogen to trigger bnAb precursors, followed by diverse boosters to enhance somatic hypermutation. This process generates bnAbs in germinal centers and memory B cells, enabling long-term protection against multiple HIV variants^[79,80^].

The findings from IAVI-G002 and IAVI-G003, the two randomized open-phase human clinical trials conducted in the United States and in Rwanda and South Africa, respectively, offer a glimmer of hope that we are closer to HIV vaccines than ever before^[80^]. The findings from IAVI-G002 and IAVI-G003 have proven the superiority of mRNA vaccines in terms of scalability, the induction of strong immune responses, and the ability to generate bnAbs^[75^], suggesting that mRNA technology is a game-changer in the quest to discover HIV-1 vaccines and would benefit humankind, especially those in endemic and underprivileged areas.

mRNA vaccines for TB treatment

Current situation on TB vaccines, and mRNA-based approaches on the potential role of mRNA vaccines in TB

TB remains a leading cause of morbidity and mortality in LMICs. There is a need for a clinically effective TB vaccine because the one that is now available is largely ineffective in endemic areas^[81^]. Mycobacterium bovis BCG is the currently licensed vaccine for TB, which protects against childhood TB meningitis, miliary TB disease, and leprosy, and is currently administered to 80% of infants in countries where it is part of the national childhood immunization program^[82^]. Although BCG vaccination-related adverse reactions and consequences could include supportive lymphadenitis, localized abscess, and, in rare instances, disseminated BCG, which is especially important for HIV-positive patients or infants who cannot be vaccinated with BCG. Generally, the BCG is most effective in preventing severe forms of TB in children, such as TB meningitis; of limited effectiveness against pulmonary TB in adults^[83^].

Recent research has shown that mRNA-based vaccines are safe, efficient, rapidly producible, and adaptable to emergency settings^[84^]. The vaccine technologies that have shown promise in preclinical studies include the cytomegalovirus (CMV) vector, which is a live, attenuated, persistent viral vector able to express multiple mycobacterium tuberculosis (MTB) antigens. It has been shown that engineering of the CMV vector leads to constant, low-level replication of the virus, giving sustained antigen expression and long-term immunity, making this technology highly attractive for TB vaccine development^[67,68^]. BCG vaccination remains essential in childhood globally, despite past questions about its efficacy. Recent research highlights how vaccine strain differences and resulting immune and epigenetic responses impact effectiveness. Ongoing efforts aim to improve the BCG vaccine and develop next-generation versions for more consistent protection.

mRNA-based vaccines can control TB by stimulating both humoral and cellular immune responses^[85^]. Multiple studies and trials have been conducted, and the success of LNP-formulated mRNA vaccines during the COVID-19 pandemic further highlights their relevance to TB. LNP composition significantly influences the quality of humoral responses, and mRNA vaccines have consistently demonstrated protective cellular immunity, which is essential for effective TB control^[80^]. mRNA-based vaccines are a potential development in the TB vaccine that will be superior in immunogenicity and antigen flexibility, and they can overcome shortcomings of existing vaccines, such as BCG^[86^]. The availability of positive preclinical and early clinical trials and research into the mRNA vaccine platforms proves critical to achieving global TB control and drug resistance^[29,87^].

Contribution of mRNA vaccines to TB elimination and challenges in TB vaccine development in LMICs

mRNA vaccines have the potential to play a transformative role in the elimination of TB, especially in regions with high TB burdens. Traditional TB vaccines, such as the BCG vaccine, have shown limited efficacy, especially in adults, and do not prevent the transmission of the disease^[11^]. mRNA technology offers a promising alternative by enabling the rapid development of vaccines targeting the specific antigens of Mycobacterium TB^[88^].

One major advantage of mRNA vaccines is their ability to encode multiple antigens in a single vaccine, potentially enhancing immune response^[14^]. Research has shown that mRNA vaccines targeting multiple M.tb (Mycobacterium TB) antigens can stimulate both humoral and cellular immunity, crucial for effective TB protection. This is important because TB immunity is largely dependent on CD4+ T cells, which mRNA vaccines can effectively activate^[89^]. Recent preclinical studies in mice have demonstrated that mRNA vaccines targeting antigens such as MPT83 and Hsp65 can induce significant protection against TB^[90^].

However, TB vaccine development continues to be a challenge, mainly because of the complex mechanisms of MTB infection, the difficulty in screening for specific antigens, the lack of ideal adjuvants, and the limitations of animal models. The limitations of animal models used in research, such as the lack of a perfect representation of human immunity and the inability to replicate latent TB in non-human models, hinder the development and testing of new vaccines^[91^]. MTB has evolved various strategies to evade the immune system, whereby it inhibits macrophage apoptosis and autophagy, suppresses phagosome-lysosome fusion, and manipulates host cellular functions to survive and replicate within host cells^[92^].

Additionally, the immune system’s response to MTB is highly variable and not fully understood, playing a role in the difficulty of developing an effective vaccine (McShane, 2019). Moreover, screening for specific antigens that could trigger an optimal immune response is difficult due to the complexity of MTB’s genome and antigenic variability^[93^]. Current adjuvants used in TB vaccines, such as those in the BCG vaccine, are not sufficient to induce long-lasting immunity, particularly in regions with a high TB burden^[94^]. Given these challenges, TB vaccine development requires overcoming significant scientific and logistical barriers, including the identification of novel antigens, understanding complex immune responses, and optimizing vaccine formulations that can both induce protective immunity and control latent infection.

mRNA vaccines for cancer treatment

Unlocking cancer treatment: the promise of mRNA vaccines

Therapeutic cancer vaccines, in contrast, are administered in the presence of established tumors, aiming to induce potent cellular immune responses to eliminate tumor cells and establish long-lasting immune memory, thereby reducing the risk of relapse^[95^]. The efficacy of cancer vaccines is dependent on the interplay among components of the immune system, the choice of adjuvant, and the mode of delivery; moreover, different platforms and antigen types have distinct advantages and disadvantages^[95^].

mRNA vaccines carrying sequences encoding tumor-associated antigens or TSAs can induce immune responses against tumor cells by activating T and B cells, and can further improve antitumor effects. The feasibility of this strategy has been demonstrated in various tumor types, including lung, breast, prostate, melanoma, pancreatic, and brain cancer^[96,97^]. In addition, mRNA vaccines can be combined with radiotherapy and chemotherapy to enhance the overall efficacy of these treatments^[98^].

As early as 1995, mRNA encoding luciferase or carcinoembryonic antigen was introduced into tumor immunotherapy, and researchers demonstrated its potential and obtained encouraging results^[97^]. Entering the 21st century, with the development of LNP technology, mRNA vaccines gradually entered clinical studies. In these studies, the safety and immunogenicity of mRNA vaccines were demonstrated in patients with melanoma and non-small-cell lung cancer^[99^]. In recent years, with the success of the COVID-19 mRNA vaccine, the application of mRNA vaccines in oncology, especially in personalized cancer vaccines and combination therapies with immune checkpoint inhibitors, has been further advanced. With advantages such as rapid and flexible design, strong immunogenicity, avoidance of genomic integration, and the ability to encode complex antigens, mRNA vaccines are currently considered an extremely promising method for cancer immunotherapy^[100^].

Preclinical and clinical trials

At present, several mRNA cancer vaccines are under clinical evaluation, and interesting interim results have been obtained. In a Phase I dose-escalation trial in melanoma, tumor burden was stabilized or decreased in some patients, and dose-dependent increases in IFN-α expression and strong antigen-specific T-cell responses were observed^[101^]; and a self-adjuvanted mRNA vaccine encoding PSA, PSMA, PSCA, and STEAP1 induced multi-antigen immunological responses, decreased immune escape, and significantly prolonged survival in multi-antigen responders in a Phase I/IIa trial in prostate cancer^[102^]. In a Phase I trial in advanced gastrointestinal cancers, personalized mRNA vaccines induced effective immunological activation in patients and were well-tolerated with no apparent adverse events, suggesting a potential therapeutic application^[103^]. Similarly, in a multicenter Phase I/IIa trial in non-small-cell lung cancer, an mRNA vaccine encoding five tumor antigens (NY-ESO-1, MAGE-C1, MAGE-C2, Survivin, and 5T4) exhibited an acceptable safety profile and immunogenicity, although it induced limited objective clinical responses as a monotherapy, indicating the need for optimized formulations or combination strategies^[104^].

In addition to solid tumors, mRNA vaccines are also being widely studied in hematological malignancies. In acute myeloid leukemia (AML), the WT1 (Wilms’ tumor 1) gene is frequently overexpressed. Loading DCs with WT1 mRNA via electroporation activated autologous T cells in an HLA-independent, multi-epitopic manner and induced WT1-specific CD8⁺ T-cell response to eliminate residual leukemic cells and provided a potential approach for relapse prevention and remission maintenance in AML^[105^]. In a Phase I trial in AML, DCs transfected with mRNA encoding WT1, PRAME, and CMV pp65 and matured through TLR7/8 activation were administered to patients with AML. This vaccine elicited antigen-specific CD8⁺ T-cell responses, and some patients exhibited prolonged overall survival and disease-free survival^[106^].

Accumulating preclinical and clinical evidence indicates that mRNA vaccines can induce effective antitumor immune responses. The latest advances in delivery systems, combination strategies, and the understanding of innate and adaptive immunity have also greatly promoted the development of mRNA vaccines.

However, mRNA cancer vaccines are still far from being realized due to many challenges. The immune system can recognize and kill tumor cells^[107^]. It is still challenging to identify tumor-specific mutations and predict epitopes that bind suitable HLA alleles. Moreover, it is technically difficult and costly to produce personalized mRNA vaccines on a large scale^[108^].

Other opportunities and challenges for mRNA vaccines in LMICs

Infrastructure and accessibility

mRNA vaccines hold great promise for combating infectious diseases in LMICs, but their reliance on ultra-cold storage poses logistical challenges. Research into improving their thermal stability is crucial to overcoming this barrier. Additionally, their intramuscular administration requires trained personnel and medical equipment, which are often lacking in rural and underserved areas, further complicating distribution and access^[109^]. Supporting this is the lack of road infrastructure and spotty electricity, which have rendered mRNA distribution almost impractical in the aforementioned areas^[110^]. Therefore, future research directions should focus on addressing the aforementioned challenges if this imperative modality is to revolutionize the field of immunotherapies globally, especially in underdeveloped regions.

Cost and funding

The cost of mRNA production consists of capital and operating expenses. The former relates to fixed-asset investments, whereas the latter mainly includes expenditures required for the daily operation of manufacturing facilities^[19^]. mRNA vaccine manufacturing could be rendered more affordable, particularly in lower-income settings, by focusing on core production steps, notably mRNA transcription and encapsulation^[111^]. There are limited data on the economic impact of infectious diseases, but their unpredictable transmission and high burden suggest substantial welfare losses. This is especially true in middle- and low-income countries, where such diseases are often endemic with high morbidity and mortality rates^[112^]. On the other hand, mRNA vaccine technology offers a unique opportunity to address life-threatening diseases of the nature described above, as it is entirely synthetic and can be produced on an industrial scale in a short period, safely and with relatively low production costs^[113^].

Global health policy and collaboration

Global health security relies on international collaboration to ensure access to life-saving tools like mRNA vaccines. However, high costs, cold-chain requirements, and limited production sites make this technology largely inaccessible in underprivileged regions^[114^]. The mRNA technology transfer empowers and equips beneficiaries with the necessary skills and the ability for better pandemic preparedness, prevention, and response. Furthermore, this initiative fosters an mRNA vaccine manufacturing ecosystem that can bolster research and innovation related to therapeutics for non-communicable diseases, which are also on the rise in the Global South^[115^]. Moreover, the global partnership simplifies vaccine logistics, leading to increased accessibility^[116^].

Regulatory and ethical considerations

The regulation and ethical considerations are essential to address issues related to safety, efficacy, and fair distribution that often impede the dissemination of vaccines. For instance, in a study conducted in central and eastern Europe, participants who were reluctant to receive COVID-19 vaccines expressed mistrust of pharmaceutical companies due to the rapid production of vaccines. Hence, they thought companies rushed to put the products on the market, casting doubt on the shortened regulatory processes^[117^].

Recently, the Japanese Nursing Ethics Association raised concerns about the safety of mRNA vaccines, citing their self-amplifying nature^[118^]. Although the currently approved mRNA COVID-19 vaccines are not self-amplifying, the fact that vaccines might cause potentially concerning side effects underscores the importance of adhering to standard regulations for vaccine production. The recipients of multiple doses of mRNA COVID-19 vaccines reported elevated IgG4 titers, in part because of the presence of other comorbidities, such as non-communicable diseases and infections, that might suppress immunity, highlighting the importance of elucidating the underlying causes of the observed increase in IgG4 titers^[119^]. On the other hand, vaccine attitudes tend to be more positive, and acceptability increases when trusted government officials, religious leaders, and traditional media convey such messages, highlighting the impact of tailored messages to build public trust during vaccination campaigns^[117^].

Moreover, the global dissemination of mRNA technology necessitates flexibility in intellectual property management. The developers should secure patent licenses from leading manufacturers, notably Pfizer and Moderna, as well as suppliers of essential chemicals, including LNP formulations, nucleoside alterations, the cap structure, and poly(A) tail sequences^[120^].

Future directions and research needs

The future of vaccines lies in the continued development of next-generation platforms, such as mRNA, DNA, and viral vector technologies, which offer rapid production, scalability, and the potential for broad-spectrum protection against emerging pathogens. Research into novel adjuvants, delivery systems, and nanoparticle-based formulations is essential to enhance immune responses, increase durability, and improve vaccine effectiveness across diverse populations. Additionally, the expansion of thermostable and temperature-resilient vaccines can reduce dependence on traditional cold chain systems, increasing accessibility in resource-limited and remote settings. Moreover, to enhance thermal stability, research should focus on optimizing the formulation of LNPs to withstand high-temperature environments. To support local production, the establishment of regional technology transfer centers, such as the African mRNA Vaccine Centers, should be promoted to enhance regional manufacturing capacity. Regarding public acceptance, it is recommended that community-based messaging trials be implemented and their effectiveness in improving vaccine uptake be evaluated.

Vaccines will play a critical role in pandemic preparedness and in combating AMR. Future research should prioritize the development of vaccines targeting novel infectious agents and antibiotic-resistant bacteria, as well as strategies for their deployment in both human and animal populations. Integrated platforms that enable rapid vaccine design, testing, and distribution will be vital for responding effectively to future outbreaks and global health emergencies.

To harness the full potential of vaccines, collaborative efforts across governments, international organizations, and the private sector are needed. Investments in R&D, technology transfer, and capacity building will accelerate innovation and promote equitable access. Strengthening surveillance and monitoring systems, coupled with robust public education and engagement programs, is crucial for evaluating the impact of vaccines, addressing vaccine hesitancy, and guiding policy decisions.

Finally, global policy frameworks should emphasize equity, preparedness, and innovation. Incentivizing vaccine research, supporting universal vaccination initiatives, and ensuring equitable distribution through programs are critical steps toward enhancing global health security. Continued research and interdisciplinary collaboration will be essential to meet evolving infectious disease challenges and achieve a resilient and inclusive immunization landscape.

Conclusion

This review underscores the escalating global health crisis posed by the dual burden of communicable and non-communicable diseases in LMICs, a challenge exacerbated by fragile healthcare infrastructures and limited access to effective prevention tools. Our analysis reveals that mRNA vaccine technology has transformative potential to address this crisis. mRNA platforms offer unmatched speed, adaptability, and scalability for developing vaccines targeting high-burden diseases such as malaria, HIV, TB, and even virus-induced cancers. Despite their promise, critical implementation barriers remain, particularly in low-resource settings, including cold-chain requirements, logistical constraints, and cost barriers. Nonetheless, early clinical data in areas like HIV and cancer immunotherapy demonstrate that mRNA vaccines can induce strong, targeted immune responses, opening doors to personalized medicine and more effective population-level disease control.

Given the profound implications for global health, it is imperative that stakeholders, including governments, international organizations, researchers, and private industry, mobilize to close the equity gap in mRNA vaccine access and infrastructure. Investment in localized manufacturing, cold-chain innovations, and strategic public-private partnerships must be prioritized to ensure that mRNA technologies are not confined to high-income nations. As we stand on the brink of a new era in vaccinology, a coordinated global effort is urgently needed to harness the full potential of mRNA vaccines to combat the evolving health threats in LMICs.

Ethical approval

Ethics approval was not required for this review.

Consent

Informed consent was not required for this review.

Sources of funding

There was no grant, technical, or corporate support for this study.

Author contributions

F.P. and G.M. contributed to the conception, data analysis, interpretation of data, drafting, revising of the manuscript, and supervision. Q.N., S.N., Y.J., S.A., R.I.S., F.A., F.K., B.A., W.M., and B.S. contributed to data analysis, drafting, and revising of the manuscript. J.H. contributed to the conception, draft review, editing, and supervision. All authors have read and approved the final version of the manuscript for submission.

Conflicts of interest disclosure

The authors declare no conflicts of interest.

Research registration unique identifying number (UIN)

The study is not registered.

Guarantor

Faida Paison.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Data sharing does not apply to this article as no new data were created or analyzed in this study.