As gp was firstly applied as antigen for EBV vaccine design, gp modification to promote immunization efficacy was also a focus during the early exploration of protein-based vaccines against EBV. In the late 20 th century, soluble gp protein was successfully expressed as a vaccine antigen Subsequent attempts to enhance the immunogenicity and improve the immunization efficacy aimed to increase the valency or target the protein to antigen presenting cells APCs using a variety of methods such as multimerization, nanoparticle assembly and fusion-protein design.
For multivalency, tetrameric gp was designed by fusing two separate gp 1— to a C-terminal leucine-zipper with or without T cell epitopes, and the results showed that tetrameric gp could elicit higher neutralizing antibody titers than monomeric gp Additionally, by fusing gp to ferritin or encapsulin, multivalent gp nanoparticles 49 were generated and immunization of mice or monkeys showed that nanoparticles elicited much higher neutralizing antibody titers than soluble monomeric gp Further, virus challenge experiments also demonstrated that gp nanoparticles provide better protection against EBV infection and improve the survival of challenged monkeys.
In addition, the fused protein simplified the purification and detection. Comparatively few studies investigated using other glycoproteins or latent phase proteins as antigens. Trimeric gHgL constructed by fusing gHgL to a C-terminal trimeric T4 bacteriophage fibritin and native trimeric gB were also tested as immunogens 51 , and the results showed that trimeric gHgL could elicit higher neutralizing antibody titers than monomeric gHgL.
Instead of using the full length or a major segment of the protein, some studies attempted to use specific epitopes as antigens to induce site-specific immune responses and thereby achieve accurate immunization. Jerome et al. Afterwards, Zhang et al. The rapid and successful application of nucleic-acid SARS-CoV-2 vaccines demonstrated their great potential in viral vaccine development. This method, based on synthetic nucleic acids, enables large-scale manufacturing with almost perfect uniformity.
Despite such advantages, the use of synthetic nucleic acids for EBV vaccine development is still in the early exploration phase. Krzysztof et al. Adjuvants incorporated in components of the antigen for vaccine formulation can modulate the immune response.
In addition to the original immunogenic profile of the selected antigen, a carefully selected adjuvant can broaden the use or enhance the efficacy for immunization. The development of gpbased vaccines inspired the exploration of adequate adjuvants for EBV vaccines. Some may show superior immunization efficacy compared to unadjuvanted gp as immunogen, since an immunization trial of unadjuvanted gp subunit vaccine on cotton-top tamarins gave unsatisfactory results, with no protection against incidence of malignant lymphoma in spite of eliciting antibodies against gp With the use of more complicated adjuvant systems in recent years, a higher immunization efficacy achieved in preclinical studies supports the case for further clinical trials.
However, due to the paucity of studies on other protein-based immunogens as vaccines against EBV, only a limited number of adjuvants were tested. For example, the VZV gE-based vaccine Shingrix was the first clinically approved herpesvirus vaccine providing protection against herpes zoster in older adults and immunosuppressed patients, while containing only VZV glycoprotein gE adjuvanted with AS01b Although VZV gE was not used as a prophylactic vaccine antigen to prevent VZV infection, an appropriate combination with the adjuvant made gE into an ideal antigen , with benefits for controlling latent VZV infection.
This result was based on a systematic screening of appropriate adjuvant systems This study also offers insights for EBV vaccine development, confirming that smart selection of adjuvants can also contribute to the development of a powerful vaccine against EBV by enhancing both initial protection from primary infection and secondary protection from reactivation or expansion of latent infection.
Therefore, an appropriate platform and adjuvant systems also determine the immunization efficacy of the vaccine, and not just the antigen. The COVID pandemic exemplifies the effective and rapid development of vaccines against broadly distributed infectious pathogens. Both mature, extensively tested technologies like inactivated virus and emerging technologies like mRNA vaccines 98 , 99 gave satisfactory results, demonstrating the unlimited opportunities of the available vaccine design platforms and encouraging further comparative studies on the use of a variety of platforms for EBV vaccine development.
For virus-based vaccines, breakthroughs in the mass production of live EBV could be a solution for inactivated vaccine development, since the latency-preference and complicated induction procedures seriously hinder its manufacture.
For the emerging protein- or nucleic acid-based vaccines, convenient modification of antigens to strengthen their immunogenicity and viable co-valency of multiple antigens to broaden the immune response spectrum are promising future approaches for vaccine development. Since the licensed VZV vaccine took the first step in clinical herpes virus immunization, it has brought home the lesson that appropriate adjuvants used in vaccine formulation can greatly enhance the immunization efficacy.
Additionally, the rising application of specific toll-like receptor TLR agonists — provides additional alternatives in the selection of adjuvants to achieve specific immunization responses. Animal models are necessary and critical for the evaluation of infection or protection status against infectious disease pathogens and developing therapeutic drugs or vaccines.
During the evaluation of vaccines against most pathogens, challenge experiments in animal models are considered the gold standard for the final assessment of vaccine efficacy — However, due to the restricted host tropism of EBV, a human herpesvirus, there is a limited range of susceptible candidate animal models — Figure 3.
Figure 3 Animal models for EBV vaccine evaluation. Non-human primates are marked in light blue and other animal models are marked in light green. LCV, lymphocryptovirus. In the late 20 th century, the discoverer of EBV, Epstein et al. By contrast, rhesus macaque, as one of the Old World NHPs, has enjoyed broad use as an animal model for a variety of human viral infections, mostly due to its relatively larger population and successful artificial breeding.
Although it is susceptible to its species-specific LCV rhLCV , which shares a high level of genomic sequence similarity with EBV , EBV cannot stably infect and immortalize the B cells of rhesus macaques , which restricts the use of this animal model in challenge experiments. Therefore, the majority of EBV immunization studies used rhesus macaques as the animal model for evaluation of specific T cell responses 45 , — Singh et al.
As the most widely used animal model, mice play an important role in EBV vaccine evaluation. Most prophylactic EBV vaccine studies used mouse immunization to primarily assess the serum antibody titer and neutralizing antibody titer 43 , 44 , However, because mice cannot be naturally infected with EBV, humanized mice are used as an alternative animal model for EBV challenge experiments 37 , 48 , These chimeric animals are constructed by transferring human CDpositive hemopoietic stem cells into immunocompromised mice , This model is appropriate for evaluating the efficacy of therapeutic treatment for immediate EBV challenge, rather than the eliciting of an adaptive immune response by a prophylactic EBV vaccine, since the mice have an incomplete immune system even after reconstitution and lack human epithelial cells.
Some studies also used rabbits as animal models for EBV vaccine evaluation 22 , 27 , 28 , 51 , 56 , , The uncertainty of the infection status hindered the use of rabbits as a challenge model, and most research studies only used rabbits as an immunization model for serum response evaluation Recently, it was found that the Chinese tree shrew Tupaia belangeri subsp. The negative staining for EBV markers in the lungs and nasopharynx also indicated that epithelial cell infection might also be absent in the tree shrew animal model , After confirming the design of a vaccine and immunization methods, assessment of immune protection efficacy would be critical for vaccine evaluation For prophylactic vaccines against infectious pathogens, the key index revealing the efficacy of immunization protection is the neutralizing antibody nAb titer , , since neutralizing antibodies can efficiently block the virus from interacting with the host receptor, preventing viral attachment and membrane fusion.
Therefore, a higher anti-EBV neutralizing antibody titer indicates better protection against EBV infection and could theoretically also reduce the incidence of EBV-associated malignancies. Although the presence of neutralizing antibodies is theoretically sufficient evidence for protection against viral infection, the value of this index in predicting the incidence of malignancies remained unclear , A large cohort study conducted in Taiwan indicated that EBV B cell neutralization capability of the serum or the anti-gp antibody titer was associated with lower risk of nasopharyngeal carcinoma.
However, Zhu et al. During the evaluation of immune reaction against EBV, the T cell response is also considered critical part, especially for eliminating latent infection and adaptive immune responses against EBV-associated tumors 58 , 60 — 62 , , A review concluded that T cell responses participate in the control of EBV in all phases of infection , However, the majority of vaccine studies evaluating the T cell response were based on latent-phase proteins such as LMP and EBNA, while studies on T cell responses induced by EBV glycoproteins or T cell epitope mapping for glycoproteins were relatively rare.
Thus, further studies on the T cell response elicited by EBV glycoproteins for controlling both primary infection and regulating immunological surveillance against EBV-associated malignant diseases could provide guidance for improving the evaluation systems for the assessment of prophylactic vaccine efficacy.
In recent years, prophylactic vaccines against EBV received significant attention, since the latest achievements in fundamental virology, vaccine technology and synthetic biology have brought new opportunities for vaccine development.
Early research studies on gp as a vaccine candidate revealed intrinsic shortage of gp in eliciting sufficient humoral immunity against primary infection. But still these studies become the forerunner for exploration of EBV glycoproteins as vaccine candidates. Besides glycoproteins, although immunization with lytic and latent phase proteins is not able to provide protection against primary infection, the strong T cell immune response elicited by these proteins benefits the establishment of lasting immune surveillance of EBV latent infection and reinforcement of anti-EBV immunity after primary humoral defense.
Additionally, an appropriate vaccine platform can improve the immunogenicity of certain antigens and enhance immune recognition. The adoption of protein modification via multimerization or fusion with immune cell-targeting domains may provide more possibilities for protein-based vaccines, while the application of synthetic nucleic acids as delivery systems could be the next milestone in the evolution of general vaccine design for not only EBV but all pathogens.
Beyond vaccine design, a finer system for the evaluation of vaccine efficacy is also crucial for the development of a successful vaccine. A suitable animal model for EBV challenge is required. And it remains unclear whether T cell responses should be listed in the assessment system for determining the protection efficacy of EBV prophylactic vaccines, urging more intensive research on the connection between elicited cellular immunity and protection from both primary infection and malignancies.
Clinical trials to determine if an EBV vaccine can reduce the rate of infectious mononucleosis or posttransplant lymphoproliferative disease should be performed.
The former is important since infectious mononucleosis can be associated with debilitating fatigue as well as other complications, and EBV infectious mononucleosis is associated with increased rates of Hodgkin lymphoma and multiple sclerosis. A vaccine to reduce EBV posttransplant lymphoproliferative disease would be an important proof of principle to prevent an EBV-associated malignancy.
This study showed the efficacy of a vaccine for infectious mononucleosis, reducing the proportion of symptomatic EBV infections from 10 percent in the control group to 2 percent in the vaccinated group.
An effective vaccine against mononucleosis is a promising step toward the prevention and treatment of more serious diseases associated with EBV, such as lymphoproliferative diseases or lymphomas. ScienceDaily, 11 December Infectious Diseases Society of America. Retrieved November 11, from www. This week in mSphere, In a new paper, researchers connect the onset and severity of mono to Print Email Share. Boy or Girl? The development of a vaccine for human use is a slow process.
But there has been progress. In , we obtained materials to create our candidate vaccine from an industrial partner. Soluble gp has been produced in the University of Minnesota Molecular and Cellular Therapeutics Laboratory and is ready for purification, after which preclinical testing can begin. If an IND is granted, we would launch clinical trials in summer
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