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. 2025 May 23;61(2):84–89. doi: 10.4068/cmj.2025.61.2.84

Oxidized Mannan: A Novel Adjuvant Candidate for Enhancing Immune Responses in Veterinary Rabies Vaccine

Rajab Mardani 1, Anahita Bahmanje 1, Yousef Cheraghi Kazeroni 1, Fereydoon Khoshroo 1, Bahram Roshanaie 2, Tahereh Sadeghche 3, Kourosh Pajaie 3, Seyed Nezamedin Hosseini 4, Delaram Doroud 4,✉, Maryam Shahali 1,✉
PMCID: PMC12133443  PMID: 40476209

Abstract

Rabies continues to pose a serious public health threat worldwide, with vaccination being the most effective means of prevention. However, commercially available inactivated rabies vaccines often require multiple doses and lack potent adjuvants to enhance their efficacy. This study aimed to investigate the coupling of whole inactivated rabies virus to mannan under oxidizing conditions to improve immune responses against a standard rabies vaccine. We explored the conjugation of whole inactivated rabies virus with oxidized mannan (Rab-OxMan) to enhance immune responses. Mice were immunized intraperitoneally with 350 µg of the Rab-OxMan formulation on days 1 and 7. Two weeks after immunization, serum samples were collected to measure levels of IgG, IgM, and TNF-α using ELISA. The vaccine’s potency was also evaluated using the National Institutes of Health (NIH) assay. Our findings showed a significant increase in IgG levels and a decrease in IgM levels in the Rab-OxMan group compared to the Alum-adjuvanted vaccine group (p<0.05). Additionally, TNF-α levels were notably higher in the Rab-OxMan group (p<0.05). Statistical analysis revealed that IgG levels had the highest sensitivity and specificity, with a significant correlation between the measured variables. Importantly, the Rab-OxMan formulation provided 1.8 times greater protection in challenge tests compared to the alum-adjuvanted group. This study is the first to demonstrate that oxidized mannan can serve as a novel adjuvant for veterinary rabies vaccines. The results highlight significant improvements in the immunogenicity and efficacy of rabies vaccines, suggesting a promising strategy for enhancing rabies prevention and potentially reducing the incidence of this deadly disease.

Keywords: Rabies Vaccine, Oxidized Mannan, NIH, Immunogenicity

INTRODUCTION

Rabies is one of the humanity’s oldest infectious diseases. The virus claims approximately 60,000 human lives annually and also causes an economic loss of 8.6 billion USD per year globally.1 An estimated number of 10 million people receive post-exposure treatments each year after being exposed to animals suspected to be infected with rabies.2 The development of the first rabies vaccine by Pasteur successfully reduced the incidence of rabies, but the disease has not been eliminated because it is maintained in many animal reservoirs.3 Many researchers have attempted to produce an affordable and safe rabies vaccine, and the currently recommended inactivated rabies vaccine adjuvanted with aluminum hydroxide gel, the most common adjuvant, which only induces T helper cell type 2 (Th2) immune responses.4 Therefore, new adjuvants are required to increase the immunogenicity of inactivated rabies vaccines.

Various carbohydrates such as β-glucan, mannan, and monophosphoryl lipid A (MPLA) can activate the immune system and induce T helper cell type 1 (Th1) immune responses,5,6 therefore, they are attractive immune adjuvant candidates. They may be used alone or in combination with other adjuvants such as Alum. Carbohydrates can be readily metabolized or degraded in vivo and are less likely to generate long-term toxicity.7 With their biocompatibility, low toxicity and ease of modification, carbohydrates have been studied as carriers for antigen delivery,8 which can often induce immune cell targeting and provide self-adjuvanting activities for a successful vaccination.

Mannan, a polysaccharide derived from the structure of plants as well as cell wall of yeasts, fungi and bacteria, contains mostly β-1,4-linked mannose backbone with a small number of α-1,6-linked glucose and galactose side chain residues.9 The carbohydrate can be recognized through binding with mannose recognition lectins presented on macrophages and other immune cells, which activates the host immune system via a non-self-recognition mechanism.10,11 The recognition initiates a set of signal transduction events leading to cytokine secretion, complement activation and CD8+ T cell activation.12 Although natural carbohydrates can be applied as vaccine components directly,13 in many cases, chemical modification of carbohydrates and/or covalently conjugates of antigens and adjuvants is necessary for enhanced efficacy.14 This can be beneficial in multiple ways, such as prolonged circulation and controlled release, size-induced lymph node targeting, better immune recognition through multivalency, enhanced cell uptake and immune activation. Two strategies (oxidative or reductive) for linking mannan to Antigens have been investigated, which induced drastically different types of immune responses.15,16 The conjugation strategy has been applied in many studies including vaccines against cancer and influenza such as breast cancer antigen, Mucin1,17 PCV2 protein of porcine circovirus type 2 virus (PCV2),18 secreted listeriolysin O (LLO) protein of Listeria monocytogenes,19 and inactivated H1N1 influenza virus20 for investigation of the enhancement of the immune responses. Based on previous reports, our studies focused on investigation of the inactivated rabies virus conjugated to oxidized mannan to its vaccine efficacy.

MATERIALS AND METHODS

1. Cell, virus, and mice

BHK-21 C13 cells, obtained from the Institute Pasteur (Alborz, Iran), were used in this study. Pasteur strain PV fixed rabies virus, adapted to grow in BHK-21 cells (PV/BHK-21) and provided by the Institute Pasteur (Alborz, Iran), was used throughout this study. All mice were outbred female SW1 sourced from the Research and Production Complex of Pasteur Institute of Iran (Alborz, Iran). All mouse-work was conducted at the Animal laboratory of quality control department of the Research and Production Complex of Pasteur Institute of Iran (Alborz, Iran), in accordance with an animal ethics application approved by the Iranian Animal Ethics Committee.

2. Cell culture

BHK-21 Cells were grown in Dulbecco’s Modified Eagle’s Medium (DMEM; Invitrogen) supplemented with fetal Bovine serum (FBS; 5-10%; Invitrogen, USA) and tryptose phosphate (TP; 0.2-0.3% w/v; Invitrogen, USA).

3. Virus production and inactivation

BHK-21 cells were infected by the rabies virus strain PV/BHK-21 at a cell concentration of 2-3×106 cells/mL, with a multiplicity of infection (MOI) equal to 0.1/cell in a 10-L bioreactor containing 7 L of DMEM (Invitrogen, USA), supplemented with tryptose phosphate (TP; 0.2-0.3% w/v; Invitrogen, USA). For the rabies virus production step, pH was maintained at 7.4, pO2 at 30% air saturation, agitation rate at 40 rpm and temperature at 37℃. The cell suspensions were centrifuged at 750-850 g for 10 min and the viral supernatants (harvests) were first clarified by filtration through a 0.8-micron filter and then inactivated by 3 mM of Binary ethyleneimine (BEI) (Sigma, USA).

4. Rabies-mannan conjugate

Whole inactivated rabies was conjugated to oxidized mannan described in Stambas et al.19 Briefly, mannan (Sigma; USA) (1 mL of 14 mg/mL) in 0.1 M phosphate pH 6.0 was oxidized with the addition of 0.1 M sodium periodate (100 µL in water) in the dark at 4℃ for 1 hr. The mixture was quenched with 10 µL ethandiol and reacted for a further 30 min as before. The oxidized mannan mixture was passed through a PD10 column (GE Biosciences) pre-equilibrated with 0.05 M bicarbonate pH 9.0 to remove by-products. The eluted 2 mL fraction of oxidized mannan (≈7 mg/mL) after void volume (2.5 mL) was collected. Each milliliter of the whole inactivated rabies virus bulk was separately reacted with 0.5 mg/mL Al (OH)3 gel (Croda; Denmark), 100 µg of filter-sterilized mannan (Sigma; USA), or 350 µg of filter-sterilized oxidized mannan for 16 h at 20℃ in 100 rpm and the resulting preparations were analyzed for its vaccine safety and potency.

According to previous studies, the periodate oxidation condition for mannan was chosen such that aldehyde residues are generated from only a fraction of oxidized mannose units of the mannan, without affecting its C-type lectin binding activity.21 For a complex antigen such as a whole inactivated rabies virus, we expect the majority of conjugation of mannan aldehyde groups to take place only at the exposed amino groups, forming Schiff base linkages.

5. Inactivity test

A 0.03 mL of the inactivated bulk rabies vaccine was intracerebrally administered to each of ten SW1 female mice, with body weights ranging from 11 to 15 g. The animals are observed for 21 days. If more than two animals die during the first 48 hours, the test is repeated. The vaccine complies with the test if, from the day 3 to day 21 post-injection, the animals show no signs of rabies and immunofluorescence test carried out on the brains of the animals show no indication of the presence of rabies virus.22

6. Safety test

1 mL of the formulated bulk rabies vaccine was injected intraperitonealy into each of eight female SW1 mice, each weighing 17–22 g. The animals are observed for 21 days. The animals are observed at least daily for 14 days. The vaccine complies with the test if no animal shows adverse reactions or dies of causes attributable to the vaccine.22

7. Serological test

In the serological test, ten female SW1 mice, each weighing 13-16 g are used. Each mouse is vaccinated by an intraperitoneal route using 0.5 mL of 1/5 of the recommended dose volume at day 0 and 7. Blood samples are taken 14 days after the first injection and the sera are tested individually for IgG, IgM, and TNFα by quantitative enzyme-linked immunosorbent assay.23

8. Potency test

In addition to Serological assays, potency was analyzed according to the National Institutes of Health (NIH) test recommended by the WHO. Mice were immunized on day 0 and 7 with 0.5 mL/dose of all experimental and reference groups via intraperitoneal (IP). Both the experimental vaccines and international reference standard rabies vaccine were diluted in a serial 5-fold dilution (1/25, 1/125, 1/625). All mice were then challenged on day 14 via an intracerebral administration (IC) of 30 µL rabies strain CVS11 (Pasteur Institute of Iran, Alborz, Iran) containing 42 LD50. Subsequently, mice were observed for another 14 days, and the mortality of mice was recorded to calculate the ED50 that is normalized with international reference standard vaccine using by using the Spearman–Karber formula to obtain a titer in IU NIH/dose. The Ph. Eur. Biological Reference Preparation (BRP) Batch Number 5 for rabies vaccine (inactivated) for veterinary use (EDQM) was used to calibrate the test. The potency is expressed in International Units/mL (IU/mL).24

9. Statistical analysis

Statistical analysis was performed using one-way ANOVA using GraphPad Prism (version 8.0, GraphPad Software, CA, USA) and statistical analyses were performed using SPSS statistics software version 26.0 (IBM, USA). All titrations were carried out in triplicate, and titers are expressed as mean values±standard deviation (SD). The comparison between groups was considered statistically significant if p<0.05 or 0.001. Furthermore, receiver operating characteristic (ROC) curves were utilized to evaluate the sensitivity and specificity of the diagnostic test, while multivariable logistic regression analysis was employed to examine the association between the predictor variables and the outcome variable.

RESULTS

1. IgG and IgM assay

As shown in Fig. 1A, mice immunized with the conjugate of inactivated rabies virus and oxidized mannan (Rab-OxMan) exhibited a significantly higher IgG titer (12.09±0.94 mg/mL) compared to those receiving mannan (Rab-Man) (11.01±0.65 mg/mL) and the Alum-adjuvanted inactivated rabies vaccine (Rab-Al) (7.94±0.71 mg/mL), with a p-value of less than 0.05 indicating statistical significance. The elevated IgG response is promising, as higher IgG levels are often correlated with enhanced protection and long-term immunity against pathogens. Conversely, as illustrated in Fig. 1B, the Rab-OxMan group showed a significantly lower IgM titer (0.54±0.05 mg/mL) than both the Rab-Man (1.03±0.10 mg/mL) and Rab-Al groups (0.72±0.07 mg/mL), with p-values<0.05. This reduction in IgM, while statistically significant, suggests a potential trade-off, as IgM is typically the first antibody produced in response to infection, reflecting early immune activation.

FIG. 1. The IgG (A) and IgM (B) titers in vaccinated mice with three types of inactivated rabies vaccines (n=10) were determined by enzyme-linked immunosorbent assay (ELISA). The mean IgG (12.09) and IgM (0.54) titers in the mice sera immunized with Rab-OxMan were significantly higher and lower, respectively, than those in mice immunized with other formulation (p<0.05). The IgG (6.29±0.39 mg/mL) and IgM (0.39±0.09 mg/mL) of the inactivated rabies virus bulk without any adjuvant “B” was measured as a control group.

FIG. 1

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These results indicate that although the Rab-OxMan formulation effectively induces a stronger IgG response, which is beneficial for long-term efficacy, it is associated with a reduced IgM response compared to other vaccine formulations. Further investigations are needed to evaluate the longevity of the IgG response and its correlation with long-term protection, as well as to understand the implications of the lower IgM response in the context of overall vaccine efficacy.

2. TNFα assay

In this assay, serum levels of TNF-α, measured by ELISA, were significantly higher in mice vaccinated with Rab-OxMan (47.67±13.1 pg/mL) compared to those immunized with Rab-Man (27.0±8.7 pg/mL) and Rab-Al (24.33±6.2 pg/mL), p<0.05. These results, depicted in Fig. 2, demonstrate that immunization with the Rab-OxMan vaccine leads to an increased TNF-α level compared to the other groups, highlighting its potential effectiveness in eliciting a robust immune response.

FIG. 2. The amount of TNF-α was measured in the sera of mice from the indicated groups (n=10) using a commercial TNF-α ELISA kit at day 14 post-immunization. The TNF-α level of the inactivated rabies virus bulk without any adjuvant “B” (20.33 pg/mL) was checked as a control group. One-way ANOVA followed by Tukey’s HSD test, *p<0.05.

FIG. 2

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3. Sensitivity and specificity analysis of the variables

The specificity and sensitivity of the sera IgG, IgM and TNFα levels were assessed using a receiver operating characteristic (ROC) curve. Areas under the curve (AUCs) and p-values were obtained as AUC=0.895 and p<0.001 for IgG, AUC=0.827 and p<0.001 for IgM, and AUC=0.752 and p<0.001 for TNF-α (Fig. 3). According to the results, the sera IgG levels demonstrated the highest sensitivity and specificity compared with other variables.

FIG. 3. The ROC curve demonstrated the behavior of the sera IgG, IgM, and TNFα sensitivity and specificity.

FIG. 3

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4. Relationship between immunogenicity variables

The logistic regression analysis revealed significant associations among the immunogenicity variables, including IgG, IgM, and TNF-α serum levels, with p-values<0.001 for all relationships analyzed. Specifically, p-values were less than 0.001 in the comparisons of IgG with IgM, IgG with TNF-α, and IgM with TNF-α, indicating robust and statistically significant correlations. These results suggest that as serum levels of IgG and IgM increase, there is a corresponding rise in TNF-α levels. The p-value of <0.001 indicates a strong likelihood that these associations are not due to random chance (Table 1). Overall, these findings underscore the interconnected nature of immune responses, suggesting that elevated levels of IgG and IgM may influence TNF-α activity, thus playing a crucial role in the overall immunogenicity observed in the study.

TABLE 1. Logistic regression results between the variables.

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5. Challenge (NIH) test

The protective activity of inactivated rabies virus samples was determined according to the NIH test. Based on the results, Rab-OxMan vaccine induced the highest potency (6.27 IU/mL) than the the Rab-Man (4.21 IU/mL) and Rab-Al counterpart (3.48 IU/mL) (Fig. 4). Significantly, the mice receiving Rab-OxMan and Rab-Man vaccines resulted in an increase of ~1.8-fold and 1.2-fold in the vaccine efficacy compared to Rab-Al-vaccinated mice, respectively.

FIG. 4. Potency (NIH) assay results measuring the effectiveness of different rabies vaccine formulations. Values represent International Units per milliliter (IU/mL). Asterisks (*) denote statistically significant differences (p<0.05) between the indicated groups.

FIG. 4

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DISCUSSION

Rabies remains a critical public health concern worldwide, with more than 59,000 reported cases of rabies-related deaths annually, predominantly in developing regions.25 The primary strategy for rabies prevention is vaccination; however, the effectiveness of traditional alum-adjuvanted inactivated rabies vaccine is often hindered by the need for multiple doses and the reliance on existing adjuvants, which may not provide optimal immune responses. This calls for improvement of rabies vaccination strategies. Investigation on the other potent and novel adjutants alone or along with alum has immense potential in this regard. Hence, in the present study, we have explored the immunogenicity effect of the whole inactivated rabies virus conjugated to oxidized mannan as a novel adjuvant and compared its protective efficacy as per the NIH guidelines in outbted SW1 mice.

One of the striking findings of the current study is the significant increase in IgG levels among mice immunized with the Rab-OxMan compared to those receiving the alum-adjuvanted vaccine. Elevated IgG levels are indicative of a robust and effective humoral immune response, which is crucial for long-term immunity and protection against rabies virus infection. The concurrent observation of decreased IgM levels suggests a shift toward a more mature immune response, characterized by class switching—an essential aspect of the adaptive immune system’s efficiency in producing high-affinity antibodies.26 This transition is particularly beneficial, as Immunoglobulin G is typically associated with a more specific and durable immune protection, while IgM is often produced earlier in the immune response but provides less effective long-term protection. Moreover, the significant increase in TNF-α levels in the Rab-OxMan group points to enhanced activation of the immune response, as TNF-α is a pivotal pro-inflammatory cytokine that plays critical roles in the activation and proliferation of various immune cells.27 Higher TNF-α levels indicate a more vigorous inflammatory response that can facilitate better antigen presentation and enhance the overall immune reaction. This improved activation could be beneficial for the development of a more potent immune memory, potentially leading to better protection upon re-exposure to the rabies virus. In fact, these data strongly suggest the induction of cellular as well as humoral immunity. This bodes well for the vaccine strategy, as it is widely held that the generation of effective immunity will require induction of a functional T cell response.

The ROC plot also shows that TNF-α shows a strong and consistent increase in sensitivity, which demonstrates its reliability as a marker for. The IgG immune response shows the highest sensitivity, emphasizing its role in confirming successful immunization and long-term protection. IgM also shows reasonable sensitivity but is not as effective as TNF-α and IgG. In general, the analysis suggests that TNF-α and IgG are particularly relevant for assessing rabies vaccination outcomes and provides insights that could enhance diagnostic and vaccination tools. In addition, based on the logistic regression analysis, the interaction among three variables is statistically significant (p<0.001), indicating a strong correlation between these variables.

In addition to the immunological assessments, the results of challenge test highlight the tangible impact of the Rab-OxMan formulation on protective efficacy of rabies vaccine. Indeed, that the oxidised mannan-Rabies conjugate provided 1.8 times greater protection in challenge test compared to the alum-adjuvanted group is particularly noteworthy. This enhanced level of protection might be attributed to the synergistic effects of the inactivated virus conjugated to oxidized mannan, which may improve of the vaccine ability to elicit stronger and more comprehensive immune responses.28 The Rab-OxMan vaccine was tested for local toxicity in SW1 mice and demonstrated to be safe at doses up to five times the therapeutic level.22

Certainly, future studies should also investigate the potential mechanisms behind the immune enhancements observed with the Rab-OxMan formulation in detail, including the role of innate immune pathways and specific immune cell types involved in the response. Furthermore, the implications of this research extend beyond rabies vaccination. The approach of utilizing oxidized polysaccharides as adjuvants could be applicable to other veterinary and human vaccines, potentially leading to broader applications in vaccine development. Overall, these findings suggest that integrating oxidized mannan into rabies vaccine formulations presents a promising avenue for improving vaccination outcomes, enhancing public health responses to rabies, and potentially saving lives.

In conclusion, this study presents compelling evidence that oxidized mannan can serve as a novel adjuvant or co-adjuvant for veterinary rabies vaccines. By significantly enhancing IgG production, modulating IgM responses, and increasing pro-inflammatory cytokine levels of the Rab-OxMan formulation demonstrates substantial improvements in immunogenicity and protective efficacy of rabies vaccine. These findings suggest that incorporating oxidized mannan into rabies vaccine formulations could be a promising strategy for improving vaccination outcomes and enhancing public health efforts against rabies. Future studies should focus on further elucidating the mechanisms underlying these immune responses and evaluating the long-term efficacy of this novel vaccine formulation.

ACKNOWLEDGEMENTS

The authors wish to acknowledge Pasteur Institute of Iran for the financial support of the study (Project No. IR.PII.REC.1401.030).

Footnotes

CONFLICT OF INTEREST STATEMENT: None declared.

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