Current development of therapeutic vaccines for the treatment of chronic infectious diseases

Although many infectious diseases are acute, most of the deaths and disease caused by infections worldwide today result from chronic infections [1]. Many people around the world are suffering from chronic infectious diseases and the number is increasing, so the development of effective response strategies for chronic infectious diseases is urgent. Because chronic infectious diseases have the potential for latent infection and recurrence, it is especially important to develop treatments for the large number of already infected carriers rather than prevention for healthy people. Chronic infectious diseases are often difficult to cure with a single treatment due to the nature of the causative pathogen continuously exists in the body, and long-term treatment may lead to the development of mutant strains resistant to the treatment. In fact, there are reports of the occurrence of multidrug-resistant pathogens in many chronic infectious diseases [2, 3, 4], which suggests the limitations of drug therapy in the treatment of chronic infectious diseases.

In this situation, approaches using “therapeutic” vaccines as a treatment strategy for chronic infectious diseases have recently received attention [5]. The application of “therapeutic” vaccines utilized the body’s immune mechanism to alleviate symptoms caused by infection or prevent reactivation of infected pathogens, so therapeutic effects can be expected without concerns about drug resistance or side effects. Therefore, it is considered that using therapeutic vaccines to respond to chronic infectious diseases will overcome the limitations of existing drug treatments and enable more efficient treatment. Accordingly, in order to prepare effective response strategies for chronic infectious diseases in the future, it is necessary to accurately understand the research and development trends of therapeutic vaccines. In this review, we examine the current status of therapeutic vaccine development for each major chronic infectious disease with high clinical demand, and based on this, we will consider current issues and improvement strategies to solve them.

Human papilloma virus (HPV) is known to infect mucous squamous cells or the skin and cause warts or papillomas near the genitals, or malignant tumors in the uterus, anus, and genitals [6]. It is estimated that 4.5% of all cancers worldwide are related to HPV infection, and approximately 80% of them are known to be cervical cancer [7].

Gardasil (Merck & Co. Inc., Rahway, NJ, USA) and Cervarix (GlaxoSmithKline, London, UK) are currently being used as HPV preventive vaccines, but these vaccines are known to have little efficacy in treating patients already infected with the virus [8], and no vaccine has yet been approved for treatment. It is well known that the E6 and E7 proteins expressed during latent HPV infection induce tumorigenesis by suppressing the activities of p53 and pRB, respectively [9]. Accordingly, oncoproteins E6 and E7 are considered the two most important target antigens for HPV therapeutic vaccines and are widely used as targets for most HPV therapeutic vaccines in development. Currently, efforts are being made to develop a vaccine for the treatment of cervical cancers caused by HPV infection based on various vaccine formulations (Table 1).

Table 1
Current status of clinical trials for therapeutic vaccines targeting HPV

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Epstein-Barr virus (EBV) infection is one of the most common infections in humans and is mainly spread through saliva. Most infected patients do not show any special symptoms, but in immunocompromised patients, it can cause malignant cancers such as lymphoma, stomach cancer, and nasopharyngeal cancer. Therefore, the International Agency for Research on Cancer classifies this virus as Group 1 risk factor that is clearly carcinogenic to humans [10]. As of 2017, approximately 265,000 cases (18%) and 164,000 deaths (17%) were reported worldwide due to EBV-related lymphoma, Hodgkin’s lymphoma, nasopharyngeal cancer, and stomach cancer [11].

It is well known that latent proteins, such as EBNA1, LMP1, and LMP2, expressed during EBV latent infection, play an important role in the carcinogenesis of EBV-related tumors [12]. Accordingly, vaccines for the treatment of EBV chronic infection currently under research and development mainly uses EBV latent proteins as target antigens, and various formulations of vaccine candidates based on these antigens are currently undergoing early clinical research (Table 2).

Table 2
Current status of clinical trials for therapeutic vaccines targeting EBV

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Cytomegalovirus (CMV) mainly infects humans and non-human primates as hosts, and commonly infects people of all ages. Once infected, it remains latent for life and it is reactivated when the host’s immunity decreased, causing various symptoms [13]. It can infect most digestive organs, including the esophagus, stomach, liver, pancreas, and large intestine, and when it progresses to a serious disease, it causes ulcers, hepatitis, intestinal obstruction, and colitis [14]. Additionally, pneumonia caused by lung infection with CMV can be life-threatening, and retinitis caused by eye infection with CMV can sometimes lead to blindness [15].

Since chronic infection with CMV rarely shows symptoms during latent infection, re-infection and re-activation of the virus cause clinically important problems, so the development of therapeutic vaccines mainly targeting envelope proteins that can neutralize virus particles is currently in progress (Table 3).

Table 3
Current status of clinical trials for therapeutic vaccines targeting CMV

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Varicella zoster virus (VZV) is a pathogen that causes two diseases depending on the type of infection. Primary infection caused by VZV appears as varicella (chickenpox), but the infected virus remains latent in the dorsal root ganglia and is likely to reactivated mainly in immunocompromised patients or those in their 50s or older, resulting in shingles (herpes zoster) [16]. The annual incidence of shingles around the world is 1.2 to 3.4 cases per 1,000 people, and is known to exceed 10 cases per 1,000 people over the age of 75 years. The lifetime risk of developing shingles is estimated to be 10%–20% [17, 18]. Clinical symptoms of shingles appear over a broad spectrum, from pain without rash to mild rash to severe rash with dissemination. In immunocompromised patients, it can cause serious neurological diseases such as outer retina necrosis that causes vision loss, gastrointestinal diseases, and angiopathy [19]. In addition, postherpetic neuralgia (PHN) is a representative aftereffect of shingles and is a neuropathic pain syndrome that occurs about a month after the onset of shingles. PHN is often severe and the incidence is known to increase with age [20].

Varicella and shingles are caused by the infection with the same pathogen, so basically, the same vaccine can be used for each infection. However, in order to suppress the viral recurrence that causes shingles, a much higher dose of antigen must be used than to prevent initial infection. Therefore, it is necessary to distinguish between varicella and shingles vaccine. The currently approved shingles vaccine (treatment vaccine) shows a dose level about 14 times higher than the shingles vaccine (preventive vaccine) [21].

Currently, two live-attenuated vaccine (ZOSTAVAX; Merck & Co. Inc. and SKYZoster; SK Bioscience, Seongnam, Korea) and a recombinant vaccine (SHINGRIX; GlaxoSmithKline) are most widely used as approved shingles vaccine. Due to the safety issue, the demand for the use of subunit vaccines such as SHINGRIX is increasing, and additional shingles vaccines using various subunit formulations are under way in clinical trials (Table 4).

Table 4
Current status of clinical trials for therapeutic vaccines targeting VZV

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Herpes simplex virus (HSV) mainly infects the skin and mucous membranes, and is divided into type 1 (HSV-1) and type 2 (HSV-2). Therefore, HSV-1 is generally associated with oral and eye diseases but the ratio of sexually transmitted diseases due to HSV-1 tends to increase [22]. On the other hand, HSV-2 is one of the world’s most widespread sexually transmitted diseases, with approximately 23 million new infections reported to occur every year [23]. According to World Health Organization (WHO), it is estimated that up to 192 million people were infected with genital HSV-1 and up to 491 million people were infected with HSV-2 in 2016 [24]. Because the clinical treatment demand for genital herpes is higher than that for other herpes, the need to develop a therapeutic vaccine targeting HSV-2 compared to HSV-1 tends to be more emphasized.

After primary infection, HSV remains dormant or latent in the host’s ganglia and can be periodically reactivated to cause chronic infection [25]. Since HSV does not show any special clinical symptoms during latent infection, it is possible to develop an HSV therapeutic vaccine that basically target the same antigen as the prophylactic vaccine. To effectively suppress HSV reactivation, many research is underway to discover target antigens that can induce a strong neutralizing immune response. Furthermore, due to the nature of viruses that infect mucous membranes, specific formulations and inoculation routes that can induce mucosal immunity are also considered important factors. Currently, several clinical trials for the development of therapeutic vaccine targeting HSV are underway (Table 5).

Table 5
Current status of clinical trials for therapeutic vaccines targeting HSV

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Hepatitis B virus (HBV) is a virus that causes acute and chronic hepatitis B, and is spread through infected blood or body fluids [26]. It is estimated that more than 2 billion people are infected with HBV worldwide, of whom approximately 250 million are chronically infected with hepatitis B [27].

Chronic HBV infection is defined as HBV persisting for more than 6 months with hepatitis B surface antigen (HBsAg) detected in the blood [26]. In the case of chronic infection with HBV, the immune response (especially T cell response) of the infected person is weakened and dysfunction occurs [28], so complete clearance of the HBV genome in chronic HBV patients is considered impossible. Therefore, the ultimate goal of a therapeutic vaccine for chronic HBV infection is proposed to be “functional treatment” that overcomes the decline in HBV-specific T cell function in chronic carriers. Currently, a therapeutic vaccine for chronic HBV patients developed as a virus-like particle formulation has been approved for use in Cuba [29], and several other vaccine candidates are currently undergoing clinical trials (Table 6).

Table 6
Current status of clinical trials for therapeutic vaccines targeting HBV

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Tuberculosis (TB) is a representative bacterial chronic infectious disease caused by infection with Mycobacterium tuberculosis. It mainly infects the lungs and causes respiratory diseases. In addition, bacterial invasion into other organs can cause meningitis, pleurisy, and peritonitis [30]. In the latent infection state, there are no symptoms, but when the infected patient’s immunity weakens, the infected pathogen progresses to active TB [31]. According to the WHO, the number of TB patients worldwide in 2022 was 10.6 million, an increase of 4.5% compared to the previous year (10.1 million). Additionally, the number of deaths due to TB was 1.6 million, a 6.7% increase compared to the previous year (1.5 million) [32].

TB treatment requires fairly long-term antibiotic administration, but the emergence of antibiotic-resistant strains is becoming more frequent, which poses a major obstacle to treating chronic TB. In addition, the BCG (Bacillus Calmette-Guérin) vaccine, the only approved TB vaccine, has been reported to be not very effective in adolescents or adults [33], so there is a great need to develop a new vaccine suitable for treating chronic TB. Accordingly, efforts are continuing to develop new therapeutic vaccines targeting chronic and latent TB infection (Table 7).

Table 7
Current status of clinical trials for therapeutic vaccines targeting tuberculosis

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Therapeutic vaccine is a relatively recent concept, and so far, there has been a tendency to focus on cancer treatment (therapeutic cancer vaccines) targeting neo-antigen of malignant neoplasms rather than infectious diseases. On the other hand, the research and development trends of therapeutic vaccines targeting infectious diseases are still relatively insufficient compared to prophylactic vaccines. Numerous prophylactic vaccines have already been approved for use, and many clinical trials of vaccine candidates are in progress. However, there are still no vaccines for the treatment of chronic infectious diseases, only except for the shingles vaccines, and the number of development studies that have entered clinical trials is very limited.

There are several factors contributing to the relative lack of development of therapeutic vaccines for chronic infectious diseases. First of all, in the case of chronic infectious diseases, the clinical manifestations of chronic infectious diseases vary depending on the characteristics of the pathogens, and as a result, the main targets of therapeutic vaccines also show very different aspects depending on the subject. Because vaccines with different therapeutic targets inevitably require different approaches to factors such as development strategy, vaccine efficacy evaluation technology, and clinical approval standards, therapeutic vaccines should be grouped according to the target symptoms and mechanism of action of the vaccine. Therefore, it is necessary to conduct research on vaccine development and evaluation methods appropriate for the characteristics of each chronic infection. The groups of therapeutic vaccines proposed in this study are as follows: (1) vaccine for symptomatic treatment, (2) vaccine to prevent recurrence, and (3) vaccine for remission (elimination) of infectious agents.

The absence of standardized immunogenicity analysis techniques for therapeutic vaccines is another factor that needs to be addressed. Appropriate treatment of a disease that has transitioned into a chronic infection requires a method that can directly kill the infected cells. Since cellular immunity plays a major role for this, in is necessary to standardize the evaluation method for T cell immune response in order to develop a therapeutic vaccine. However, unlike humoral immunity, the measurement of cellular immunity requires experimentally complex processes and equipment, and because the activity of cellular immunity shows very large variations for each individual/period/tissue, there are still no clear standard protocols and procedures.

Nevertheless, it has been confirmed that global efforts are being made to develop therapeutic vaccines based on various formulations for representative chronic infectious diseases with high clinical demand. In particular, due to the recent success of messenger RNA (mRNA) vaccines in coronavirus disease 2019 pandemic, new possibilities for vaccine development against various infectious diseases that have long been considered incurable are being presented, and development efforts are being attempted by applying mRNA formulations to therapeutic vaccines. Research on therapeutic vaccines based on the mRNA platform is currently undergoing clinical trials for most of the chronic infectious diseases investigated in this study, and it is expected that this novel platform can play a positive role in the development of therapeutic vaccines in the future.

In order to develop a successful therapeutic vaccine, along with the progression of vaccine formulation technology and immunotherapy technology, standardization of test methods and the establishment of evaluation standards to verify the efficacy of vaccine substances are additional elements that must be established. To achieve this, research on the pathological characteristics of each chronic infectious disease and an accurate understanding of the immunological factors necessary for defense/treatment of each chronic infection are prerequisite. It also includes efforts to discover latent infection and reactivation-specific antigens, develop cell-mediated immunogenicity measurement technology, and establish standard/reference materials. If these current issues are shared at the national level with academia and industry, and research capabilities are focused and supported in necessary areas, it is expected that effective responses to chronic infectious diseases through therapeutic vaccines will be possible in the future.