1 Introduction

Mosquito-borne diseases are a significant global health concern, affecting millions of people annually. These diseases are caused by various pathogens, including viruses from the Togaviridae and Flaviviridae families, which are transmitted by mosquito vectors such as Aedes aegypti and Aedes albopictus (Bettis et al., 2022). Notable diseases include Dengue, Zika, Chikungunya, and Yellow Fever, which have led to numerous outbreaks and substantial morbidity and mortality worldwide (Huang et al., 2023). The epidemiology of these diseases is influenced by factors such as climate change, global travel, and urbanization, which facilitate the spread of mosquito vectors to new regions, thereby increasing the risk of disease transmission (Näslund et al., 2021).

Developing vaccines for mosquito-borne diseases presents several challenges. One major issue is the genetic diversity of the viruses, which complicates the creation of vaccines that provide broad protection. For instance, the Dengue virus has four serotypes, and infection with one serotype does not confer immunity against the others, leading to the risk of severe disease upon secondary infection (Huang et al., 2019). Additionally, the unpredictable nature of outbreaks and the sporadic occurrence of these diseases make it difficult to conduct large-scale vaccine efficacy trials. Furthermore, the rapid emergence and re-emergence of these pathogens outpace the development of effective vaccines and treatments, necessitating continuous research and innovation (Kim, 2018).

Focusing on emerging mosquito-borne pathogens is crucial due to their potential to cause significant public health crises (Brugueras et al., 2020). Recent outbreaks of Zika and Chikungunya viruses have highlighted the need for effective vaccines to prevent widespread transmission and mitigate the impact on affected populations. Emerging pathogens often exploit gaps in existing public health infrastructure, leading to rapid and uncontrolled spread. Moreover, the adaptation of mosquito vectors to new environmental conditions and their ability to invade new regions underscore the urgency of developing vaccines that can be deployed quickly in response to emerging threats (Teramoto et al., 2019).

This study provides a comprehensive overview of the current state of vaccine research for emerging mosquito-borne pathogens. It will examine the various vaccine platforms under development, including inactivated vaccines, viral-vector vaccines, live attenuated vaccines, protein vaccines, and nucleic acid vaccines1. It will also identify the key challenges and gaps in current research efforts and propose future directions to enhance vaccine development and deployment. By synthesizing the latest findings and insights from multiple studies, this study seeks to inform and guide future research initiatives aimed at combating mosquito-borne diseases effectively.

2 Historical Context and Lessons Learned

2.1 Review of past vaccine development efforts

The development of vaccines for mosquito-borne diseases has a long and complex history, marked by both significant achievements and notable challenges. Malaria remains a significant global health challenge, particularly in sub-Saharan Africa, where it causes substantial morbidity and mortality (Wang, 2024). Early efforts focused on diseases such as yellow fever and malaria, with varying degrees of success. For instance, the RTS,S/AS01 (RTS,S) vaccine for malaria, developed in recent years, represents a milestone in the fight against Plasmodium falciparum malaria, although it does not offer protection against Plasmodium vivax malaria (Manning et al., 2020). In the case of dengue, the CYD-TDV vaccine has been licensed, but its efficacy and safety have been subjects of ongoing research and debate. More recently, the TAK-003 tetravalent dengue vaccine has shown promising results in phase 3 trials, demonstrating an overall efficacy of 80.9% in preventing virologically confirmed dengue (Huang et al., 2019).

2.2 Successes and failures in mosquito-borne disease vaccines

The journey of vaccine development for mosquito-borne diseases is punctuated by both successes and failures. The development of the yellow fever vaccine in the 1930s stands out as a significant success, providing long-lasting immunity and drastically reducing the incidence of the disease. Similarly, the RTS,S malaria vaccine, despite its limitations, represents a significant advancement in malaria control (Benelli and Mehlhorn, 2016). However, the path has not been without failures. The CYD-TDV dengue vaccine, for example, faced significant setbacks due to safety concerns, particularly in seronegative individuals, which led to severe disease outcomes in some cases. The challenges in developing effective vaccines for diseases like Zika and chikungunya also highlight the complexities involved. Despite ongoing efforts, no licensed vaccines are currently available for these diseases, although several candidates are in various stages of development (Biswal et al., 2019).

2.3 Impact of historical vaccines on public health

The impact of historical vaccines on public health has been profound. The yellow fever vaccine, for instance, has been instrumental in controlling outbreaks and preventing the spread of the disease in endemic regions. Similarly, the introduction of the RTS,S malaria vaccine has the potential to significantly reduce malaria morbidity and mortality, particularly in sub-Saharan Africa (Bettis et al., 2022). The development and deployment of the TAK-003 dengue vaccine could also have a substantial impact on public health, given its high efficacy in preventing symptomatic dengue and reducing hospitalizations (Achee et al., 2019). Moreover, the ongoing research into vector-targeted vaccines, such as the AGS-v vaccine targeting mosquito saliva proteins, represents a novel approach that could further enhance our ability to control mosquito-borne diseases. In summary, the historical context of vaccine development for mosquito-borne diseases provides valuable lessons. While there have been notable successes, the journey is fraught with challenges that require continuous innovation and adaptation. The impact of these vaccines on public health underscores their importance in the ongoing fight against mosquito-borne diseases.

3 Emerging Mosquito-Borne Pathogens

3.1 Identification and characterization of emerging pathogens

Emerging mosquito-borne pathogens such as dengue virus, chikungunya virus, and Zika virus have been identified as significant threats due to their rapid spread and severe health impacts. These viruses have been characterized by their ability to adapt to new environments and hosts, facilitated by global travel and trade. The chikungunya and Zika viruses, for instance, have shown remarkable adaptability, with chikungunya causing millions of infections globally and Zika leading to significant public health concerns due to its association with congenital abnormalities. The identification of these pathogens involves understanding their viral biology, historical transmission routes, and the mechanisms that facilitate their rapid global invasion (Mordecai et al., 2019).

3.2 Epidemiological trends and threat assessment

The epidemiological trends of mosquito-borne diseases indicate a rising incidence and geographic spread, driven by factors such as climate change, urbanization, and increased human mobility. For example, the resurgence of dengue in tropical and subtropical regions and the spread of West Nile virus and Japanese encephalitis to new habitats highlight the dynamic nature of these diseases. The threat assessment of these pathogens involves analyzing climatic and environmental variables, such as temperature and precipitation, which are key factors influencing the distribution and transmission of mosquito vectors (Figure 1) (Bartlow et al., 2019). Additionally, the socioeconomic changes and land-use patterns significantly contribute to the changing epidemiology of these diseases (Franklinos et al., 2019).

Bartlow et al. (2019) found that the integration of multiple models—climate, terrestrial, mosquito, and epidemiological—is crucial for accurately predicting the risks associated with mosquito-borne diseases. The climate model influences the mosquito habitat and population dynamics by simulating events such as inundation and vegetation changes. These environmental factors directly impact mosquito breeding sites and, subsequently, the spread of diseases. Additionally, the terrestrial model contributes by modeling vegetation and its effects on mosquito habitats, while the mosquito model focuses on population dynamics. The epidemiological model further incorporates the movement of animal and human populations, which are essential for understanding disease transmission patterns. The interaction and data flow between these models, validated by real-time ground truth data, ensure that the risk predictions are robust and actionable. The holistic approach enables better preparedness and response strategies for managing the public health impacts of mosquito-borne diseases.

3.3 The role of climate and environmental changes in pathogen emergence

Climate and environmental changes play a crucial role in the emergence and re-emergence of mosquito-borne pathogens. Rising global temperatures, altered precipitation patterns, and increased frequency of extreme weather events create favorable conditions for mosquito breeding and virus transmission (Marchi et al., 2018). For instance, temperature changes can affect the vital rates of mosquitoes and the pathogens they carry, with transmission peaking at specific temperature ranges. Moreover, climate change can lead to the introduction of competent mosquito vectors into temperate regions, thereby expanding the geographic range of diseases like dengue and West Nile fever (Weissenböck et al., 2010). The interaction between climate change and other global processes, such as land-use changes and urbanization, further complicates the dynamics of mosquito-borne disease transmission. In conclusion, the identification and characterization of emerging mosquito-borne pathogens, understanding their epidemiological trends, and assessing the impact of climate and environmental changes are critical for developing effective vaccine strategies and mitigating future outbreaks. Continued research and investment in surveillance, vector control, and vaccine development are essential to address the evolving threat of these diseases (Shragai et al., 2017).

4 Innovative Approaches in Vaccine Research

4.1 Advances in genomic and proteomic technologies

Recent advancements in genomic and proteomic technologies have significantly enhanced our understanding of mosquito-borne pathogens and their interactions with hosts. These technologies enable the identification of novel antigens and the development of more targeted vaccines. For instance, the use of cryo-electron microscopy has allowed for detailed structural analysis of viral proteins, facilitating the design of vaccines that can elicit strong immune responses (Jiang et al., 2021). Additionally, the integration of genomic data has been pivotal in the development of multivalent DNA vaccines, which can target multiple pathogens simultaneously, as demonstrated in proof-of-concept studies involving mosquito-borne and hemorrhagic fever viruses (Manning et al., 2020).

4.2 Utilization of mRNA vaccines and novel platforms

The emergence of mRNA vaccine technology represents a groundbreaking advancement in the field of vaccinology. mRNA vaccines have shown great promise due to their ability to induce robust immune responses and their rapid development timelines. Recent studies have highlighted the efficacy of mRNA vaccines in combating various infectious diseases, including those caused by mosquito-borne pathogens (Whitehead et al., 2017). Innovations in mRNA delivery systems and production protocols have further enhanced the stability and immunogenicity of these vaccines, making them a viable option for future vaccine development6. Additionally, novel platforms such as insect-specific virus-based chimeric vaccines have demonstrated safety and efficacy in preclinical models, offering new avenues for vaccine design.

4.3 Development of multivalent and universal vaccines

The development of multivalent and universal vaccines is a critical area of research aimed at providing broad protection against multiple strains or species of pathogens. Multivalent vaccines, such as the tetravalent dengue vaccine, have shown promising results in clinical trials, eliciting strong immune responses against all four dengue virus serotypes. Similarly, DNA vaccines targeting multiple mosquito-borne viruses have demonstrated the potential to generate long-term immune memory and neutralizing activity against various pathogens. The concept of universal vaccines, which aim to provide protection against a wide range of related viruses, is also gaining traction. For example, the use of chimeric vaccines based on insect-specific viruses has shown potential in providing durable protection against lethal alphavirus challenges (Pardi et al., 2020).

4.4 Integration of novel adjuvants and delivery systems

The incorporation of novel adjuvants and delivery systems is essential for enhancing the efficacy and safety of vaccines. Adjuvants such as Montanide ISA 51 have been used to boost the immunogenicity of peptide-based vaccines, as seen in trials involving mosquito saliva proteins8. Advanced delivery systems, including in vivo electroporation and nanoparticle-based carriers, have been employed to improve the delivery and expression of vaccine antigens, resulting in stronger and more durable immune responses (Erasmus et al., 2017). These innovations are crucial for the development of next-generation vaccines that can effectively combat emerging mosquito-borne pathogens. In summary, the future of vaccine research for emerging mosquito-borne pathogens lies in the integration of cutting-edge genomic and proteomic technologies, the utilization of novel vaccine platforms such as mRNA and insect-specific viruses, the development of multivalent and universal vaccines, and the incorporation of advanced adjuvants and delivery systems. These innovative approaches hold the promise of providing effective and long-lasting protection against a wide range of mosquito-borne diseases (Figure 2) (Huang et al., 2023).

Huang et al. (2023) demonstrated that the development of CHIKV vaccines involves various strategies utilizing different platforms, including DNA plasmids, infectious DNA (iDNA), and viral vectors. The VRC-CHKVLP059-00-VP candidate utilizes a plasmid DNA approach to express CHIKV structural proteins in human cells, which is a key step in eliciting an immune response. The pCHIKV-7 candidate, on the other hand, is based on iDNA technology, encoding the full-length genome of a live attenuated CHIKV clone, which mimics natural infection to stimulate immunity. The MV-CHIKV vaccine candidate leverages a measles virus vector to deliver CHIKV structural genes, while the adenovirus-based candidates (Ad-CHIKV-SG, Ad-CHIKV-E3/E2/E1, and Ad-CHIKV-E3/E2/6K) focus on delivering specific structural protein sets to enhance immune targeting. These diverse approaches underscore the complexity and multi-faceted nature of vaccine design aimed at effectively combating chikungunya virus.

5 Challenges in Vaccine Development

5.1 Antigenic variability and immune evasion strategies

One of the primary challenges in developing vaccines for emerging mosquito-borne pathogens is the high antigenic variability and immune evasion strategies employed by these pathogens. For instance, pathogens like the dengue virus exhibit significant genetic diversity, which complicates the development of a universal vaccine that can provide broad protection against all serotypes (Kim, 2018). Additionally, the rapid mutation rates of these viruses enable them to evade the host immune response, making it difficult to achieve long-lasting immunity. This necessitates continuous monitoring and updating of vaccine formulations to keep pace with the evolving pathogens (Manning et al., 2020).

5.2 Vaccine delivery and distribution in resource-limited settings

Effective vaccine delivery and distribution in resource-limited settings pose another significant challenge. Many regions affected by mosquito-borne diseases lack the necessary infrastructure for proper vaccine storage and distribution, which can compromise vaccine efficacy (Amorij et al., 2012). Innovative delivery methods, such as needle-free injections and thermostable formulations, are being explored to address these issues. However, the implementation of these technologies requires substantial investment and logistical planning to ensure that vaccines reach the populations most in need (Trovato et al., 2020).

5.3 Ethical considerations and public acceptance

Ethical considerations and public acceptance are critical factors that influence the success of vaccination programs. The rapid development and deployment of vaccines, especially during outbreaks, raise ethical concerns regarding informed consent, equitable access, and the potential for adverse effects. Public skepticism and misinformation about vaccine safety can also hinder vaccination efforts, as seen with the COVID-19 pandemic. Engaging with communities, transparent communication, and addressing ethical concerns are essential to build public trust and ensure the success of vaccination campaigns (Gebre et al., 2021). In summary, addressing the challenges of antigenic variability, improving vaccine delivery in resource-limited settings, and navigating ethical considerations and public acceptance are crucial for the successful development and implementation of vaccines against emerging mosquito-borne pathogens. These efforts require a multidisciplinary approach, combining scientific innovation with effective public health strategies to protect vulnerable populations from these diseases (Jiang, et al., 2021).

6 Case Study

6.1 Case study: development of a vaccine for zika virus

The Zika virus (ZIKV) has emerged as a significant public health concern, particularly due to its association with severe congenital disabilities such as microcephaly in newborns. Despite the urgency, there is currently no effective vaccine available for ZIKV. Research efforts have been initiated to develop a vaccine, with several candidates in various stages of development. The challenges in Zika vaccine development include the need for a vaccine that is safe for pregnant women and provides long-lasting immunity. The molecular characteristics of ZIKV, such as its ability to cross the placental barrier, further complicate vaccine development (Silva et al., 2018).

6.2 Case study: ongoing efforts in developing a vaccine for chikungunya virus

Chikungunya virus (CHIKV) is another mosquito-borne virus that has caused significant outbreaks, particularly in tropical and subtropical regions. The virus is known for causing severe joint pain, which can persist for months or even years, significantly impacting the quality of life of affected individuals. Despite the high disease burden, there are no licensed vaccines for CHIKV. Several vaccine candidates are currently in preclinical and clinical trials, with some reaching Phase II trials. The development of a CHIKV vaccine faces several hurdles, including the need for a vaccine that can provide long-term immunity and the challenge of conducting efficacy trials due to the sporadic nature of outbreaks (Figure 3) (Cunha et al., 2020).

Cunha et al. (2020) identified key mechanisms in the chikungunya virus (CHIKV) lifecycle that highlight the virus's ability to manipulate host cellular processes. CHIKV's entry into mammalian cells, facilitated by clathrin-dependent and independent endocytosis, leads to the formation of replication complexes anchored at the plasma membrane, initiating viral RNA synthesis. The study also emphasizes the virus's impact on cellular stress responses, including ER stress and oxidative stress, which activate the Unfolded Protein Response (UPR) and autophagy. These stress responses are crucial for maintaining cell viability but also play a role in CHIKV pathogenesis by promoting viral replication and contributing to inflammation. Additionally, CHIKV's ability to trigger the NLRP3 inflammasome and subsequent activation of caspase 1 links the virus to inflammatory disease symptoms such as edema and arthritis, underscoring its potential to cause severe pathogenic effects in infected individuals.

6.3 Case study: innovative approaches in dengue vaccine development

Dengue virus (DENV) presents a unique challenge for vaccine development due to its four distinct serotypes. Infection with one serotype provides immunity to that serotype but increases the risk of severe disease upon subsequent infection with a different serotype. The first licensed dengue vaccine, Dengvaxia®, has shown efficacy in preventing severe dengue and hospitalization in seropositive individuals but has limitations, including its restricted age range and the need for prior exposure to the virus. Other vaccine candidates are in advanced stages of development, including those by NIAID/Instituto Butantan and Takeda, which are in Phase III trials. Innovative approaches, such as recombinant tetravalent vaccines, are being explored to address the complexities of dengue virus immunity and provide broader protection (Kantor, 2018). In summary, while significant progress has been made in the development of vaccines for Zika, Chikungunya, and Dengue viruses, several challenges remain. Continued research and innovative approaches are essential to overcome these hurdles and develop effective vaccines to control these emerging mosquito-borne pathogens (Roth et al., 2014).

7 Future Directions in Vaccine Research

7.1 Integration of artificial intelligence and machine learning

The integration of artificial intelligence (AI) and machine learning (ML) in vaccine research holds significant promise for accelerating the development of vaccines against emerging mosquito-borne pathogens. AI and ML can be utilized to predict potential vaccine candidates, optimize vaccine design, and analyze large datasets for epidemiological modeling. For instance, a study demonstrated the use of a deep learning approach to design a multi-epitope vaccine for SARS-CoV-2, which could be adapted for mosquito-borne diseases. Additionally, leveraging satellite Earth Observation data with AI and ML algorithms has shown potential in developing accurate epidemiological models for diseases like malaria, dengue, and West Nile Virus, which can inform vaccine development and deployment strategies (Parselia et al., 2019).

7.2 Personalized vaccination strategies

Personalized vaccination strategies are emerging as a crucial area of research, aiming to tailor vaccines based on individual genetic, immunological, and environmental factors. This approach can enhance vaccine efficacy and safety by considering the unique responses of different populations. For example, the development of a tetravalent dengue vaccine showed varying efficacy trends based on serotype and baseline serostatus, highlighting the need for personalized approaches in vaccine administration. Personalized strategies could also involve the use of DNA vaccines, which have shown versatility and long-term immune memory in preclinical studies, suggesting their potential for rapid deployment in response to multiple concurrent epidemics.

7.3 Global collaboration and data sharing in vaccine research

Global collaboration and data sharing are essential for advancing vaccine research and addressing the challenges posed by emerging mosquito-borne pathogens. Collaborative efforts can facilitate the sharing of epidemiological data, research findings, and technological advancements, thereby accelerating vaccine development and deployment. The success of integrated vector management strategies and the evaluation of new vector control tools underscore the importance of global cooperation in combating mosquito-borne diseases. Furthermore, initiatives like the Worldwide Insecticide resistance Network (WIN) exemplify the benefits of international collaboration in addressing public health challenges.

7.4 Potential for cross-protective vaccines targeting multiple pathogens

The development of cross-protective vaccines that target multiple mosquito-borne pathogens is a promising direction for future research. Such vaccines could provide broad protection against various diseases transmitted by the same vector, thereby simplifying vaccination programs and enhancing public health outcomes. For instance, multivalent DNA vaccines have shown robust immune responses against multiple viral antigens in preclinical studies, indicating their potential to combat concurrent epidemics of mosquito-borne and hemorrhagic fever viruses. Additionally, vector-targeted vaccines, such as those targeting mosquito salivary proteins, have demonstrated safety and immunogenicity in humans, suggesting a viable approach for reducing the burden of vector-borne diseases. By exploring these future directions, vaccine research can make significant strides in preventing and controlling emerging mosquito-borne pathogens, ultimately improving global health outcomesv (Yang et al., 2020).

8 Concluding Remarks

The research on vaccines for emerging mosquito-borne pathogens has made significant strides, yet several challenges remain. Various vaccine platforms, including inactivated, viral-vector, live attenuated, protein, and nucleic acid vaccines, are being developed to combat viruses such as Dengue, Zika, and Chikungunya. The development of a mosquito saliva peptide-based vaccine has shown promise in early trials, demonstrating safety and immunogenicity in humans. The emergence and re-emergence of mosquito-borne arboviruses like Chikungunya and Zika highlight the need for new strategies in disease control and vaccine development. Despite the promising candidates, no licensed vaccines are available for many of these diseases, underscoring the need for continued research and development. The use of multivalent DNA vaccines has shown potential in generating robust immune responses against multiple mosquito-borne viruses. Additionally, advancements in vaccinomics and the discovery of novel mosquito-associated viruses provide new avenues for vaccine development.

Future vaccine research should focus on several key areas to address the challenges posed by emerging mosquito-borne pathogens. First, there is a need to accelerate the development and clinical testing of promising vaccine candidates, particularly those that have shown efficacy in preclinical studies. The use of innovative platforms such as DNA vaccines and vaccinomics can help in the rapid development of effective vaccines. Additionally, exploring vector-targeted vaccines, such as those targeting mosquito saliva proteins, could provide a novel approach to disease prevention. Collaborative efforts between nations, international organizations, and the private sector are essential to overcome financial and logistical barriers to vaccine development. Finally, continuous surveillance and research into newly discovered mosquito-associated viruses will be crucial in anticipating and mitigating future outbreaks.

To effectively combat emerging mosquito-borne pathogens, a coordinated and multifaceted approach is required. Policymakers and funding agencies must prioritize and invest in vaccine research and development, ensuring that promising candidates can move swiftly through the clinical trial phases. There is also a need for international collaboration to share data, resources, and expertise, particularly in regions most affected by these diseases. Public-private partnerships should be encouraged to stimulate innovation and investment in vaccine technologies. Additionally, integrating vector control strategies with vaccine deployment can provide a comprehensive approach to disease prevention. Finally, public health policies should be updated to incorporate the latest scientific advancements and ensure that new vaccines are accessible to populations at risk.

Acknowledgments

Thanks to the peer reviewers for their suggestions on this study.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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