J. Microbiol. Infect. Dis., (2026), Vol. 16(3): 160-164

Review Article

10.5455/JMID.2026.v16.i3.5

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Insights into human immune response to Rubella virus infection

Balid Albarbar*

Department of Medical Laboratory, Higher Institute of Sciences & Medical Technology, Alkums, Libya

*Corresponding Author: Balid Albarbar. Department of Medical Laboratory, Higher Institute of Sciences & Medical Technology, Alkums, Libya. Email: B.albarbar [at] yahoo.co.uk

Submitted: 15/01/2026 Revised: 06/06/2026 Accepted: 16/06/2026 Published: 20/08/2026

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ABSTRACT

Rubella virus (RV), also known as German measles, is a member of the Togaviridae family and is the causative agent of rubella. Despite the availability of an effective vaccine, rubella remains a significant global public health concern, particularly due to its teratogenic effects when contracted during pregnancy. Pregnant women who contract rubella in the first trimester can experience miscarriage or congenital rubella syndrome. Understanding the intricacies of the human immune response to rubella is essential for optimizing vaccination strategies and controlling outbreaks. This paper briefly reviews the current state of knowledge regarding the immune response to RV, including the mechanisms of innate and adaptive immunity, immune memory, vaccine-induced immunity, and correlates of protection. Furthermore, the implications of immune evasion mechanisms employed by the virus are explored, and avenues for future research to improve vaccine efficacy and control the transmission of rubella are discussed.

Keywords: Immune evasion, Immune memory, Immune response, Rubella virus, Vaccination.

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Introduction

Rubella is a vaccine-preventable disease caused by the rubella virus (RV). It is characterized by a mild fever accompanied by a rash (Deguchi, 2010). However, the significance of rubella lies in its potential complications, particularly congenital rubella syndrome (CRS), when it is contracted during pregnancy (Rima and Duprex, 2006; Medu et al., 2024).

Rubella disease is no longer considered endemic in the United States. However, rubella remains a significant global health issue in other countries with low vaccination coverage. In the WHO African Region, surveillance data from 2022 to 2023 reported 4,805 confirmed rubella cases. Despite the availability of a safe and cost-effective vaccine, there were an estimated 17,865 rubella cases in 78 countries in 2022, according to the WHO. Globally, it is estimated that approximately 100,000 babies are born with CRS each year as a result of rubella infection. Up to 4 babies per 1,000 live births were affected by CRS before rubella vaccination was introduced. Despite the availability of a safe and effective vaccine, rubella remains endemic in many countries, necessitating ongoing efforts to understand the human immune response to RV for improved vaccination strategies (Zimmerman et al., 2022).

This study briefly highlights the current state of knowledge regarding the human immune response to rubella infection, the mechanisms through which immunity is acquired, and the role of vaccination in preventing rubella and its associated complications. In addition, the implications of immune evasion mechanisms employed by the virus are explored, and avenues for future research to improve vaccine efficacy and control rubella transmission are discussed.

Pathogenesis and CRS

Rubella is a highly contagious airborne disease that is primarily transmitted through respiratory droplets. Upon entering the respiratory tract, it replicates in the nasopharynx and subsequently spreads to the bloodstream, causing viremia and reaching various tissues, including the skin, lymph nodes, and placenta, as previously described (Das and Kielian, 2021; Komal et al., 2024). The characteristic disease rash appears several days after infection and is a hallmark of the disease. The mild symptoms of rubella in healthy individuals contrast sharply with the devastating effects it can have on fetal development when infection occurs during pregnancy (Komal et al., 2024).

Regarding the pathogenesis of CRS, RV crosses the placenta during viremia in early pregnancy (Pereira, 2018). After infection of the respiratory tract and systemic dissemination, circulating RV reaches the placental intervillous space, where maternal blood contacts the trophoblast layer (Lambert et al., 2015a,b; Pereira, 2018). The RV can infect placental cytotrophoblasts, leading to cytopathic effects and cell death that compromise the syncytiotrophoblast barrier that normally separates maternal and fetal blood. Infected trophoblasts and damaged placental architecture allow the RV to traverse the maternal–fetal interface and enter the fetal circulation. The RV replicates in multiple organ systems, including the developing heart, eyes, and central nervous system, within the fetus (Oster et al., 2010; Oh et al., 2025). The cellular mechanisms of teratogenesis include the inhibition of intracellular actin assembly and mitosis, leading to impaired precursor cell development, apoptosis induction in infected cells, and cytokine and interferon signaling dysregulation. These effects disrupt normal organogenesis, particularly during the critical first and second trimesters, when developmental processes are most sensitive to teratogenic insult (Pitchaikani et al., 2025). Vertical transmission rates are highest early in gestation and decline after 20 weeks, reflecting the maturation of placental barrier functions and reduced fetal tissue susceptibility as development progresses (Pereira, 2018; Das and Kielian, 2021).

Innate immune response to RV

The RV is an enveloped virus, single-stranded, positive-sense ssRNA (Mangala Prasad et al., 2017). There are three immunologically relevant structural proteins: E1 glycoprotein (a major neutralizing antigen), E2 glycoprotein, which contributes to immune recognition, and Capsid (C) protein (an internal T-cell antigen) (Chen and Icenogle, 2006; Das and Kielian, 2021). Upon RV infection, the innate immune system serves as the first line of defense, triggering a cascade of events aimed at limiting viral replication and initiating adaptive immunity (Kilich et al., 2024). The key components of the innate immune response include pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), which recognize viral components and initiate antiviral signaling pathways leading to the secretion of type I interferon and proinflammatory cytokines, including IL-6, TNF-α, and IL-1β (Ovsyannikova et al., 2010; Schilling et al., 2022). Innate immune cells, including dendritic cells (DCs), macrophages (Mϕ), and natural killer cells (NKs), play crucial roles in viral clearance. However, rubella has evolved mechanisms to evade certain aspects of the innate immune response, allowing the virus to persist long enough to induce adaptive immunity (Stambas et al., 2020; Perelygina et al., 2021; Schilling et al., 2021).

Adaptive immune response to RV

The E1 envelope glycoprotein is a class II fusion protein containing conformational neutralizing epitopes essential for viral entry and the principal target of protective antibodies (DuBois et al., 2013). Although E2 contributes to antigenicity, E1 remains the dominant immunogen, while capsid-derived peptides primarily stimulate T-cell responses and may undergo antigenic variation, affecting immune recognition. Long-lived plasma cells and memory lymphocytes maintain durable immunity, whereas impaired antigen-specific responses permit viral persistence in congenital infection (Chaye et al., 1992; Lambert et al., 2015a,b). The adaptive immune system is activated when DCs present viral antigens to naïve T lymphocytes in lymph nodes. This process leads to the differentiation of CD4⁺ T helper cells, which then orchestrate immune responses, including the activation of cytotoxic CD8⁺ T lymphocytes and B cells (Ou et al., 1997; Stambas et al., 2020). The function of T cells is to recognize viral peptides presented by MHC molecules and contribute to the control RV infection (Ovsyannikova et al., 2005; Ovsyannikova et al., 2010; Lambert et al., 2015a,b). The role of CD8⁺ T cells in clearing rubella infections is less studied but is believed to contribute to viral clearance. CD4⁺ T helper cells are crucial in supporting B cell activation and antibody production, as well as enhancing the function of CD8⁺ T cells. Overall, the action, responses, and cooperation of B and T cells lead to the elimination of acute infection and the formation of immune memory (Wang et al., 2023).

In addition to the cellular immune response, humoral adaptive immune responses mainly include B cells that produce virus-specific antibodies (in particular, IgM and IgG) (Wang et al., 2023). The secreted antibodies neutralize the virus and facilitate its clearance. IgM is the first antibody to be detected following infection, indicating an acute infection phase. The presence of rubella-specific IgG antibodies indicates either past infection or successful vaccination and provides long-term immunity (Wandinger et al., 2011 ; Hiebert et al., 2022; Albarbar, 2024).

Prevention efforts: role of rubella disease vaccination

The rubella vaccine, which is typically administered as part of the MMR vaccine, has proven to be highly effective in preventing infection. The vaccine contains a live attenuated RV that stimulates the immune system to produce antibodies without causing disease. Vaccine-induced immunity is long-lasting, and rubella-specific IgG antibodies are detectable in individuals for decades after vaccination (Carryn et al., 2019; Vashishtha and Kumar, 2024). Immune memory ensures rapid and effective responses upon re-exposure to RV, thereby preventing neurological complications in children, conferring protection against reinfection, and reducing the risk of CRS (Motaze et al., 2021; Silva Filho et al., 2024).

Immune evasion mechanisms of the RV

The RV employs various strategies to evade host immune responses, including the inhibition of type I interferon signaling (a critical antiviral defense pathway) (Sakuragi et al., 2022) through its nonstructural proteins p150 and p90 (Stoll et al., 2024). p150 is a key antagonist in this process because it disrupts signaling pathways such as JAK–STAT, thereby suppressing the establishment of an effective antiviral state. On the other hand, p90 plays a central role in modulating innate immunity, viral replication, and persistence (Matthews et al., 2012; Sakuragi et al., 2022). The viral genome encodes these proteins as cleavage products of the p200 polyprotein, forming a functional replicase complex essential for infection (Matthews et al., 2012). Importantly, p150 and p90 localize to virus-induced membranous structures that serve as RNA synthesis sites, effectively shielding viral components from immune detection (Matthews et al., 2012; Das and Kielian, 2021). A hallmark of RV infection is its ability to establish persistent infection, particularly in fetal tissues, resulting in CRS (Das and Kielian, 2021).

Taken together, RV immune evasion is mediated through the following pathways: (1) suppression of interferon signaling, (2) sequestration of viral replication complexes, (3) regulation of apoptosis, and (4) impairment of host immune cell function. These integrated mechanisms are critical for viral persistence and pathogenesis, particularly in patients with congenital infection.

Challenges and future directions

Despite the availability of a safe and effective vaccine for rubella, several challenges remain in understanding and maintaining long-term immunity against the RV. Vaccination has largely reduced the global rubella disease burden; however, rubella continues to cause outbreaks in areas with inadequate vaccine coverage and causes CRS. According to the World Health Organization, in 2022, an estimated 17,865 rubella cases were reported across 78 countries worldwide, indicating that global elimination has not yet been achieved.

One of the major challenges is the variability in vaccine-induced immune responses among vaccinated individuals. Although most vaccinated individuals develop protective antibodies, some experience low antibody titers or become seronegative years after vaccination. Studies have shown that a small proportion of individuals fail to develop adequate immunity after vaccination (primary vaccine failure) (Marohl et al., 2025), while others experience a gradual decline in antibody levels over time (secondary vaccine failure) (Marohl et al., 2025). This variation complicates the assessment of long-term protection, particularly among women of reproductive age, which increases the risk of CRS during pregnancy (Marohl et al., 2025).

The next challenge is the limited understanding of the immune mechanisms responsible for effective protection. Current assessments mainly rely on measuring rubella-specific IgG antibodies (Muscat et al., 2024). However, antibody levels alone may not precisely reflect protective immunity because memory B cells and T-cell responses also play a critical role in long-term immune protection (Muscat et al., 2024). Therefore, individuals with low antibody levels may still possess effective immune memory, whereas others may remain susceptible to previous vaccination.

Intervention studies have demonstrated that rubella vaccines induce strong and long-lasting immune responses (Marohl et al., 2025). Long-term follow-up studies have reported seroconversion rates exceeding 95% after vaccination, with protective antibodies persisting for many years (Carryn et al., 2019; Muscat et al., 2024). Nevertheless, booster vaccination studies have shown that some seronegative individuals can regain protective antibody levels following additional vaccine doses, suggesting that immune memory may persist even when circulating antibodies decline (Bianchi et al., 2019; Wang et al., 2023; Nakaharai et al., 2024). These findings indicate that antibody waning does not necessarily equate to complete loss of protection but highlights the need for better correlates of immunity.

From a public health perspective, immunity gaps remain a significant obstacle to achieving rubella elimination. Insufficient vaccination coverage, disruptions caused by the COVID-19 pandemic, vaccine hesitancy, and population movement have contributed to persistent susceptibility in several regions (Nakaharai et al., 2024; Sanchez et al., 2025). Although many countries have successfully eliminated endemic rubella transmission, continued surveillance and immunization efforts are required to prevent the reemergence of rubella.

Future research should focus on identifying robust immunological correlates of protection beyond antibody titers. Advanced approaches, such as systems immunology, single-cell sequencing, and immune profiling, may improve the understanding of memory B-cell and T-cell responses following rubella infection or vaccination. In addition, studies investigating genetic factors that influence vaccine responsiveness could help explain interindividual differences in immune protection. Another important research priority is evaluating the need for targeted booster vaccination strategies in populations at increased risk of waning immunity, particularly health care workers and pregnant women.

Furthermore, strengthening global surveillance systems and improving vaccination coverage are essential for achieving elimination of rubella. The integration of immunological monitoring with molecular epidemiology may help identify gaps in immunity and guide targeted vaccination campaigns. Emerging vaccine technologies, including mRNA-based platforms, may also enhance long-term immune memory and improve vaccine accessibility in low-resource settings. Together, these advances could contribute to more effective prevention strategies and support the global goal of rubella eradication in the future (Reef et al., 2023).

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Conclusion

Understanding the human immune response to rubella is essential for devising effective vaccination strategies to control and prevent CRS transmission. Furthermore, research is needed to elucidate the mechanisms of immune protection, identify correlates of immunity, and develop novel vaccine candidates with improved efficacy and safety profiles. By leveraging our knowledge of host–pathogen interactions, we can strive toward the global eradication of rubella and its devastating consequences.

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Acknowledgments

None.

Funding

None.

Authors’ contributions

There is only one author of this review article.

Conflict of interest

The author declares no conflict of interest.

Data availability

All data are provided in the manuscript.

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References

Albarbar, B. 2024. The importance of IgM and IgG antibodies testing in infectious diseases. Libyan Med. J. 16, 84–89.

Bianchi, F.P., De Nitto, S., Stefanizzi, P., Larocca, A.M.V., Germinario, C.A. and Tafuri, S. 2019. Immunity to rubella: an Italian retrospective cohort study. BMC Public Health. 19, 1490.

Carryn, S., Feyssaguet, M., Povey, M. and Di Paolo, E. 2019. Long-term immunogenicity of measles, mumps and rubella-containing vaccines in healthy young children: a 10-year follow-up. Vaccine 37, 5323–5331.

Chaye, H.H., Mauracher, C.A., Tingle, A.J. and Gillam, S. 1992. Cellular and humoral immune responses to rubella virus structural proteins E1, E2, and C. J. Clin. Microbiol. 30, 2323–2329.

Chen, M.H. and Icenogle, J. 2006. Molecular virology of rubella virus. In Perspectives in Medical Virology. Elsevier.

Das, P.K. and Kielian, M. 2021. Molecular and structural insights into the life cycle of Rubella Virus. J. Virol. 95, e02349–20.

Deguchi, M. 2010. Rubella virus. Nihon. Rinsho. Japanese. Clin. Med. 68(6), 394–397.

Dubois, R.M., Vaney, M.C., Tortorici, M.A., Kurdi, R.A., Barba-Spaeth, G., Krey, T. and Rey, F.A. 2013. Functional and evolutionary insight from the crystal structure of rubella virus protein E1. Nature 493, 552–556.

Hiebert, J., Zubach, V., Charlton, C.L., Fenton, J., Tipples, G.A., Fonseca, K. and Severini, A. 2022. Evaluation of diagnostic accuracy of eight commercial assays for the detection of rubella virus-specific IgM antibodies. J. Clin. Microbiol. 60, e01597–21.

Kilich, G., Perelygina, L. and Sullivan, K.E. 2024. Rubella virus chronic inflammatory disease and other unusual viral phenotypes in inborn errors of immunity. Immunol. Rev. 322, 113–137.

Komal Mallikarjun, D., Kamble, H.V. and Waghmare, S.A. 2024. A comprehensive review on rubella virus.

Lambert, N., Strebel, P., Orenstein, W., Icenogle, J. and Poland, G.A. 2015. Rubella. Lancet. 385, 2297–2307.

Lambert, N.D., Haralambieva, I.H., Kennedy, R.B., Ovsyannikova, I.G., Pankratz, V.S. and Poland, G.A. 2015. Polymorphisms in HLA-DPB1 are associated with differences in rubella virus-specific humoral immunity after vaccination. J. Infect. Dis. 211, 898–905.

Mangala Prasad, V., Klose, T. and Rossmann, M.G. 2017. Assembly, maturation and three-dimensional helical structure of the teratogenic rubella virus. PLoS Pathog 13, e1006377.

Marohl, R., Mccormick, K., Okut, H., Keomany, J., Wallace, D., Grainger, D.A. and Tatpati, L. 2025. With increasing vaccination reluctance, does rubella immunity predict rubeola immunity well enough?. J. Women’s Health. 34, 973–978.

Matthews, J.D., Tzeng, W. and Frey, T.K. 2012. Determinants in the maturation of rubella virus P200 replicase polyprotein precursor. J. Virol. 86, 6457–6469.

Medu, O., Mahajan, P., Hennink, M., Stang, L., Anderson, M., Tan, B., Oyenubi, A., Plamondon, M., Salvadori, M.I., Franklin, K., Primeau, C., Hiebert, J., Minion, J. and Diener, T. 2024. Congenital rubella syndrome, a case series. Can. Commun. Dis. Rep. 50, 274–281.

Motaze, N.V., Mthombothi, Z.E., Adetokunboh, O., Hazelbag, C.M., Saldarriaga, E.M., Mbuagbaw, L. and Wiysonge, C.S. 2021. The impact of rubella vaccine introduction on rubella infection and congenital rubella syndrome: a systematic review of mathematical modelling studies. Vaccines 9, 84.

Muscat, M., Ben Mamou, M., Reynen-de Kat, C., Jankovic, D., Hagan, J., Singh, S. and Datta, S.S. 2024. Progress and challenges in measles and rubella elimination in the WHO European Region. Vaccines.

Nakaharai, K., Nakazawa, Y. and Yoshida, M. 2024. Association between rubella vaccination response and long-term immune response to severe acute respiratory syndrome coronavirus 2 after BNT162b2 vaccination. J. InfectChemotherapy. 30, 81–83.

Oh, J.K., Tsang, S.H. and Sharma, T. 2025. Rubella retinopathy. Adv. Exp. Med. Biol. 1467, 241–243.

Oster, M.E., Riehle., Colarusso, T. and Correa, A. 2010. An update on cardiovascular malformations in congenital rubella syndrome. Birth Defects Res. 88, 1–8.

Ou, D., Mitchell, L.A., Décarie, D., Gillam, S. and Tingle, A.J. 1997. Characterization of an overlapping CD8+ and CD4+ T-cell epitope on rubella capsid protein. Virology 235, 286–292.

Ovsyannikova, I.G., Dhiman, N., Haralambieva, I.H., Vierkant, R.A., O’Byrne, M.M., Jacobson, R.M. and Poland, G.A. 2010. Rubella vaccine-induced cellular immunity: evidence of associations with polymorphisms in the Toll-like, vitamin A and D receptors, and innate immune response genes. Hum. Genet. 127, 207–221.

Ovsyannikova, I.G., Jacobson, R.M., Vierkant, R.A., Jacobsen, S.J., Pankratz, V.S. and Poland, G.A. 2005. Human leukocyte antigen class II alleles and rubella-specific humoral and cell-mediated immunity following measles-mumps-rubella-II vaccination. J. Infect. Dis. 191, 515–519.

Pereira, L. 2018. Congenital viral infection: traversing the uterine-placental interface. Annu. Rev. Virol. 5, 273–299.

Perelygina, L., Faisthalab, R., Abernathy, E., Chen, M.H., Hao, L., Bercovitch, L., Bayer, D.K., Noroski, L.M., Lam, M.T., Cicalese, M.P., Al-Herz, W., Nanda, A., Hajjar, J., Vanden Driessche, K., Schroven, S., Leysen, J., Rosenbach, M., Peters, P., Raedler, J., Albert, M.H., Abraham, R.S., Rangarjan, H.G., Buchbinder, D., Kobrynski, L., Pham-Huy, A., Dhossche, J., Cunningham Rundles, C., Meyer, A.K., Theos, A., Atkinson, T.P., Musiek, A., Adeli, M., Derichs, U., Walz, C., Krüger, R., Von Bernuth, H., Klein, C., Icenogle, J., Hauck, F. and Sullivan, K.E. 2021. Rubella virus infected macrophages and neutrophils define patterns of granulomatous inflammation in inborn and acquired errors of immunity. Front. Immunol. 12, 796065.

Pitchaikani, S., Govindan, P. and Shakila, H. 2025. Maternal exposure to rubella infection elevates risk of congenital rubella syndrome (CRS). Int. Rev. Neurobiol. 501–526.

Reef, S.E., Icenogle, J.P. and Plotkin, S.A. 2023. The path to eradication of rubella. Vaccine 41, 7525–7531.

Rima, B.K. and Duprex, W.P. 2006. Morbilliviruses and human disease. J. Pathol. 208, 199–214.

Sakuragi, S., Liao, H., Yajima, K., Fujiwara, S. and Nakamura, H. 2022. Rubella virus triggers type I interferon antiviral response in cultured human neural cells: involvement in the control of viral gene expression and infectious progeny production. Int. J. Mol. Sci. 23, 9799.

Sanchez, J., Rodriguez Sr, A.A. and Cuello Sr, K.P.M. 2025. Impact of the COVID-19 pandemic on routine childhood vaccination coverage in Ecuador from 2019 to 2021: comparative analysis. JMIRx Med. 6, e75293–e75293.

Schilling, E., Grahnert, A., Pfeiffer, L., Koehl, U., Claus, C. and Hauschildt, S. 2021. The impact of rubella virus infection on a secondary inflammatory response in polarized human macrophages. Front. Immunol. 12, 772595.

Schilling, E., Wald, M.E., Schulz, J., Werner, L.E. and Claus, C. 2022. Interferon signaling-dependent contribution of glycolysis to rubella virus infection. Pathogens. 11, 537.

Silva Filho, D.G.D., Martins, G.D.S., Campos, I.S., Souza, C.D.D., Santos, L.B.M., Oliveira Junior, V.S.D., Soares, E.D.S., Leite, S.D.S.M., Barbosa, S.R.A., Soares, N.D.P., Borges, D.A., Souza Júnior, L.R.D., Andrade, K.S.D. and Rosa, R.B.R. 2024. The importance of vaccination against measles, rubella and mumps in preventing neurological complications in children. Braz. J. Implantol. Health. Sci. 6, 1164–1174.

Stambas, J., Lu, C. and Tripp, R.A. 2020. Innate and adaptive immune responses in respiratory virus infection: implications for the clinic. Expert Rev. Respiratory Med. 14, 1141–1147.

Stoll, G.A., Nikolopoulos, N., Zhai, H., Zhang, L., Douse, C.H. and Modis, Y. 2024. Crystal structure and biochemical activity of the macrodomain from rubella virus p150. J. Virol. 98, e01777–23.

Vashishtha, V.M. and Kumar, P. 2024. The durability of vaccine-induced protection: an overview. Expert Rev. Vaccines 23, 389–408.

Wandinger, K.P., Saschenbrecker, S., Steinhagen, K., Scheper, T., Meyer, W., Bartelt, U. and Enders, G. 2011. Diagnosis of recent primary rubella virus infections: significance of glycoprotein-based IgM serology, IgG avidity and immunoblot analysis. J. Virol. Methods 174, 85–93.

Wang, L., Haralambieva, I.H., Ovsyannikova, I.G., Grill, D.E., Warner, N.D., Poland, G.A. and Kennedy, R.B. 2023. Associations of adaptive immune cell subsets with measles, mumps, and rubella-specific immune response outcomes. Heliyon 9, e22998.

Zimmerman, L.A., Knapp, J.K., Antoni, S., Grant, G.B. and Reef, S.E. 2022. Progress toward rubella and congenital rubella syndrome control and elimination?worldwide, 2012-2020. MMWR. Morb. Mortal. Wkly. Rep. 71, 196–201.