The epidemiology, diagnosis and management of scrub typhus disease in China

ABSTRACT

Thirty-nine years ago, scrub typhus (ST), a disease, was not among the China’s notifiable diseases. However, ST has reemerged to become a growing public health issue in the southwest part of China. The major factors contributing to an increased incidence and prevalence of this disease include rapid globalization, urbanization, expansion of humans into previously uninhabited areas, and climate change. The clinical manifestation of ST also consists of high fever, headache, weakness, myalgia, rash, and an eschar. In severe cases, complications (e.g. multi-organ failure, jaundice, acute renal failure, pneumonitis, myocarditis, and even death) can occur. The diagnosis of ST is mainly based on serological identification by indirect immunofluorescence assay and other molecular methods. Furthermore, several groups of antibiotics (e.g. tetracycline, chloramphenicol, macrolides, and rifampicin) are currently effective in treating this disease. This fact suggests the need for robust early diagnostic techniques, increased surveillance, and prompt treatment, and develop future vaccine.

KEYWORDS:

• Scrub typhus
• Orientia tsutsugamushi
• prevalence
• diagnosis
• china

Introduction

Scrub typhus (ST) is a febrile illness caused by the Gram-negative coccobacillus bacteria Orientia tsutsugamushi that are transmitted to humans through the bites of infected larval mites known as “chiggers” (belonging to the family Trombiculide).^1,2 Furthermore, this zoonotic disease predominates in the Asia-Pacific region, including China.^3–11

Most patients with ST that receive appropriate treatment recover from this disease. However, delayed diagnosis and improper management of ST can result in severe complications and even death. Individuals with ST have clinical characteristics that resemble other diseases, such as dengue fever, malaria, leptospirosis, typhoid and other febrile illnesses. Given the overlap of symptoms among these diseases, a definitive diagnosis of ST will depend on patients’ medical history, physical examination, detailed account of clinical features and reliable diagnostic tests. A key diagnostic indicator of ST is the presence of eschar.^12–14

However, in the absence of the pathognomonic eschar, ST is mainly diagnosed on the basis of laboratory testing that involves serological assays, such as indirect immunofluorescence assay (IFA) for detecting serum IgM antibodies or a four-fold increase serum antibody titers.¹⁵ In addition, several molecular methods that target a specific O. tsutsugamushi gene, such as PCR, qPCR, LAMP among other tests, have been used to diagnosis ST.^16–22

However, it is important to note that these assays are not point-of-care methods, and they require well-equipped laboratory and technical skills.²³ The serological diagnosis’s main drawbacks include the possibility of serological diagnosis for ST among closely-related organisms and low sensitivity in the acute phase of illness, making it less useful for diagnosis and subsequent treatment. Nevertheless, when used in combination with molecular methods, can lead to a definitive diagnosis.²⁴ A point-of-care assay, such as an immunochromatographic test (ICT) or dipstick test that detects O. tsutsugamushi-specific antigens in the patient’s blood/plasma/serum, is ideal as a rapid and early diagnostic tool, particularly in rural settings or during emergency cases.^25,26 Notably, ST also can be treated successfully using antibiotics; in particular, doxycycline, tetracycline, azithromycin, and rifampicin have been applied as the first line of medications for ST treatment, but that have led to few treatment failures.^27,28 Where Chloramphenicol and tetracycline are remains a treatment option for ST patient and are resistance to conventional antibiotics,^27,29 and Macrolide antibiotic such as azithromycin were found to be highly effective against ST,³⁰ warranting the development of an effective vaccine for the disease prevention and control in the future.^31,32

The first case in China was identified in Guangzhou city, Guangdong Province, in the nineteenth century,² and a scientific report on ST was first published in 1885 during the Ming Dynasty.³³ Before 1985, ST infection was found to be endemic south of the Yangtze River;⁴ in 1986, ST was observed in the north of Yangtze River Jiangsu Province and Shandong Province.^34,35 In 2006, ST was detected in Henan province,³⁶ while an outbreak of ST occurred in Shandong and others part of China between 2006 to 2016.^37,38

The prevalence of ST has substantially increased in many parts of China.^4,39 Two species of chiggers, namely Leptotrombidium deliense and Leptotrombidium scutellare,transmit O. tsutsugamushi to humans in south and north China, respectively.⁴⁰ Despite efforts to prevent the spread of these pathogens, ST cases have been widely reported in many parts of China.^{4,5,7,31,41,42} To date, ST is one of the most pervasive zoonotic diseases in the country as reported by China’s Information System for Disease Control and Prevention (CISDCP).⁵ Thus, given its current prevalence and its various effect on individual health status, there is a need to understand the epidemiological distribution and discover ways to combat this disease.

Furthermore, a more detailed analysis of the circulating O. tsutsugamushi strains in China needs to be performed since this knowledge will likely be essential to developing an of an effective vaccine and sensitive specific point-of-care diagnostic methods. The present review focuses on the epidemiological importance of O. tsutsugamushi in China. In addition, disease transmission, diagnosis, management aspects, and the current national trends of this neglected disease will also be briefly discussed.

Scrub typhus etiology

O. tsutsugamushi is the etiologic agent of ST. Moreover, the bacteria have several biological attributes that are unique. For example, O. tsutsugamushi has a single chromosome with highly repetitive sequences and an abundance of mobile genetic elements.⁴³ This bacterial strain relies on the host cell’s microtubule trafficking apparatus for intracellular motility.⁴⁴ O. tsutsugamushi also exits the host cell by virus-like budding that involves lipid rafts,⁴⁵ and these microbes have cell walls with a minimal amount of peptidoglycan content.⁴⁶

O. tsutsugamushi was initially isolated and identified as a Gram-negative α-proteobacterium from the family Rickettsiaceaein Japan in 1930.⁴⁷ However, thecausative agent of ST, is a obligate intracellular bacteria (0.5 × 1.2–3.0 µm) with a different cell wall structure and genetic makeup to other rickettsiaee. Subsequently, the classification of O. tsutsugamushi was revised, and this organism was assigned to the genus, Orientia.⁴⁸ Numerous serotypes of O. tsutsugamushi also exist in China, including Gilliam, Kato, Karp, Hirano/Kuroki, Shimokoshi, TA763, and Irie/Kawasaki, respectively, were reported in advance as the serotype.⁵

Diseases transmission

Scrub typhus is primarily transmitted by the larvae (or chiggers) of the trombiculid mites.^41,42 which belong to the genus Leptotrombidium spp.^1,2,5,40,49 These arthropods are the vector for O. tsutsugamushiin the Asia-Pacific region. The trombiculid mites have four main developmental stages in their lifecycle: namely egg, larva, nymph, and adult with three quiescent stages. The larvae (0.2–0.4 mm in length) can only be observed through a magnifying glass or a microscope.^50–54 Furthermore, these immature mites typically feed on wild rodents (R. flavipectus, R. losea, R. confucianus, and R. norvegicus), Apodemusagrarius, and Suncus murinus.^3,55 Although humans are an incidental host of the larvae,⁵⁶ their transmission rate to humans can be influenced by climate change and rodent density.^55,57,58 O. tsutsugamushi is transmitted to mammalian hosts by the third-stage larvae mites, which feed on the extracellular fluid of vertebrates. Mites act as the primary reservoir for O. tsutsugamushi.⁵⁹ In later stage adults, mites pass on the ST-causing bacteria to their eggs in a process called transovarial transmission. Through this process, O. tsutsugamushiis maintained in the vector from one life stage to another.^60,61 The presence of chigger mites may be strongly influenced by the environment where host species live. More explicitly, prior studies have indicated that temperature is a key factor affecting the mite development and reproduction of Leptotrombidium mites (particularly, L. delicense).^50,52,62

In addition, the onset of ST has been correlated with environmental factors. For example, the temperature is argued to drive the prevalence of ST. In particular, warmer weather conditions lead to increasing the outdoor activity levels that could create opportunities for people to be more suspected to ST infection.⁶³ Furthermore, invasive plant species, such as Leucaenaleucocephala, whichare the preferred ecological habitats of Leptotrombidium mites, could result in an overabundance of O. tsutsugamushi. Lastly, the socioeconomic changes that lead to alterations in land cover along with climate variation can also culminate in the unexpected emergence of ST in humans.^62–66

Clinical manifestation and diagnosis of ST

Scrub typhus is associated with a number of clinical symptoms, the most common being an initial fever, eschar, rash, and lymphadenopathy.⁶⁷ After a 4 to 21 day incubation period, the clinical presentation of ST begins with a fever that typically ranges from 38.5°C to 42°C. The duration of the fever persists between 1 and 12 days (the average length of the period of illness of time is 4.5 days).^7,9,68 In severe cases, serious complications such as broncho-pneumonia, myocarditis, and heart failure were observed.^{58,59,63–73}

In China, clinical cases of ST are characterized by the common symptoms described above along with vomiting, splenomegaly, hepatomegaly, pneumonitis, meningitis, multiple organ dysfunction, disseminated intravascular coagulation, conjunctival congestion, fatigue and anorexia.^69,70

Although ST and dengue fever are acute febrile illnesses in Asia, they can be distinguished from one another based on the duration of fever, serum alanine aminotransferase/serum aspartate aminotransferase (ALT/AST) values, platelet count, absence of bone pain, C-reactive protein (CRP), and presence/absence of bleeding syndrome.⁶³ Furthermore, it also has been observed that lymphadenopathy and multi-organ dysfunction are common manifestations in patients with eschars. Hence, the presence of eschar can be considered an early prognostic indicator of multi-organ dysfunction in infected individuals.¹⁴

While the absence of a skin rash has been reported in some cases of ST, increased levels of serum adenosine deaminase (ADA) and ferritin has been associated with complicated forms of ST, which can lead to prolonged hospitalization.^8,74 In China, the diagnosis of ST is based on the patient’s history, clinical features and findings, and the serologic testing results.

The Chinese Ministry of Health classified ST diagnosis into three distinct categories: suspected, probable and confirmed cases. Suspected cases consist of individual who participate in outdoor activities (e.g. farming, fishing, camping, and straw collection) during the ST epidemic in China three weeks before onset of illness and presented with fever, skin rash, and lymphadenectasis. Individuals diagnosed with dengue fever, typhus fever, hemorrhagic fever, or had an uncertain history of mite bites but developed fever were excluded from this classification. Probable cases are clinically diagnosed by local physicians based on epidemiologic measures, such as travel to affected areas and contact with chiggers or rodents <3 weeks before the onset of illness. Confirmed cases are laboratory corroborated infection following the diagnosis criteria and case classification guidelines developed by the Chinese national health authorities.⁵⁷

The attending physicians are required by law to report all suspected and probable cases of ST to the Chinese Center for Disease Control and Prevention (China CDC). A diagnosis of ST is determined by local health care professionals in a hospital setting. In cases where eschars (a common indicator of ST) are absent, a laboratory test is mandatory to confirm diagnosis.²⁶ ST status can be assessed by direct (isolation and DNA detection) and indirect (serology) methods. Notably, Indirect immunofluorescence antibody assay(IFA) method, as known as serology gold standard can be beneficial for screening a large number of serum samples, however have limited its use in resource-restricted areas due to the test is more sensitive and requires propagation and purification of BSL3 agents as antigen for assay and fluorescence microscope. While serological diagnostic tests such as the Weil-Felix agglutination test were developed to identify ST cases, it has poor sensitivity and specificity for acute disease. It is requires paired samples.²⁶ Although the rapid diagnostic assays (RDTs) can be used for early diagnosis of ST, this latter test is particularly suitable as a diagnostic tool in rural areas of China.⁷⁵ In addition, several other molecular assays, such as PCR, qPCR, LAMP, and recombinase polymerase amplification can be employed to direct detectO. tsutsugamushi in clinical specimens,^{9,52,71,72,76} which can serve as a reference culture for enhanced diagnosis.

In China, the diagnosis relies mainly on laboratory tests and clinical findings. Also, the antibody-based serological tests are basis of ST diagnosis. ST diagnostic test conducted base on diagnostic performance of IFA as gold standard reference method recommended by the WHO and Weil-Felix agglutination test; this is widely used in each level of Chinese medical institutions. ELISAs as well as provide sensitive and specific test results, and PCR assays detect antibodies against O. tsutsugamushi, where more details on the evaluation of ST diagnosis in China were recently reported by Lei Xin H., et al (2019).⁷⁷

Geographic distribution and current epidemiology

Scrub typhus occurs within a 13,000,000 km² area of Asia mainly in a region known as “Tsutsugamushi Triangle” which extends from northern Japan to eastern Russia in the North and connects to northern Australia in the South and to Pakistan and Afghanistan in the West, as well as the Western Pacific islands and East Asia, including China.³ It is estimated that at least one billion people in the Asia-Pacific region are at risk of contracting this disease annually.^5,10,40,78 It is also important to note that the geographic range of O. tsutsugamushi and other closely-related species has extended beyond the Tsutsugamushi Triangle.^79-84 ST cases have been primarily found in southwest China and the southeast coastal and eastern regions of China.⁸⁰ The endemic of ST also report in Guangzhou province,⁵ and in other regions in China.^4,80 and recently reported in Jingjiang City, in south-central Jiangsu, China.⁹ Although, the current epidemiological investigations showed the ST cases decreased significantly in China.⁸¹

Epidemiology of ST in China

It is reported that ST has existed in southern China for thousands of years.^4,5 Prior to the 1980s, cases of ST were observed mainly in the south of Yangtze River regions, (e.g. Zhejiang and Yunnan provinces).⁸³ However, from 1952 to 1989, ST was reported in six provinces: Guangdong, Fujian, Yunnan, Zhenjiang, Jiangsu, and Shandong Province,³⁵ Furthermore, over the past decade alone, ST prevalencehas increased in several areas within provinces of China.⁷⁹ For example, 4,865 confirmed cases were reported in 566 locations in Jiangsu Province in 2018.⁴ The affected geographic area has rapidly expanded to encompass Taiwan, Yunnan, and Sichuan in the west, Hainan at the south, and Zhejiang and Hunan in the north, among other regions of China.⁸⁴ More recently, this disease has been widely reported in a number of provinces in China.^{4,5,9,35–39,42,64,79,85}

Since the first outbreak in Shandong Province in 1986,^83,86 ST incidence had increased in the China territories. For example, ST outbreak was reported in Jingling city, where this disease had never previously existed. Despite the current measures of prevention and control system undertaken by the China Center for Disease Control and Prevention (Chinese CDC), evidence still indicates a rapid increase in ST cases.⁵⁷ Notably, the number of ST reported cases in Guangdong and Yunnan was higher than in other provinces in China.⁸⁷ In a recent study, Yue et al. (2019) divided ST prevalence into three distinct regions in China, namely North (Anhui, Jiangsu, Shandong), Southwest (Yunnan, Sichuan), and South (Fujian, Guangdong, Guangxi, Hainan, Hunan, Jiangxi, Zhejiang) China.^35,88

Explicitly, ST is an important public health issue in the Asia-Pacific area.^10,89 However, the full extent of the global distribution of this disease outbreak and its burden is poorly understood.⁹⁰ The disease surveillance system in China was initially established in 1952.⁸⁰ When only two vectors of O. tsutsugamushi (Leptotrombidium deliense and L. scutellare mites) were known.^91,92 After 1989, ST was no longer considered a notifiable infectious disease in China; however, due to recent serious outbreaks, ST has been listed as a notifiable diseases since 2009, and the physicians in China are required by law to report ST cases that are ascertained through the primary health care center, hospital or Chinese CDC.⁵⁷

While ST is geographically occurring in waves.^40,93–95 For example, ST occurs at higher levels in individuals living in rural areas when compared to urban settings (Figure 1(b)), independently of their sex (Figure 1(a)).³⁸

Figure 1. The distribution of ST disease by sex (a), and the distribution of ST cases by region (b) in China between 2006 and 2016 (Li et al., 2020).³⁸

Scrub typhus occurs at higher levels in individuals at age more than 61 years, and lower ST cases occur among children under five years (Figure 2).³⁸

Figure 2. Age-wise distribution of ST cases stratified by age group in China from 2006 to 2016 (Li et al, 2020).³⁸

Scrub typhus occurs at higher levels in individuals living in China’s south region compared with cases in the northern part and in the southwest region (Figure 3(a)).⁹⁶ ST occurs at higher levels among the number of patients in county hospitals than the number of primary medical care cases (Figure 3(b)).⁸¹

Figure 3. Interval and average between onset and diagnosis of ST cases in high incidence regions in China (a) and the number of medical care institutions reporting ST cases in China between 2006 and 2016 (b) based on data reported by (Yujuan et al., 2020; Xin et al. 2019).^77,96

Also, ST occurs at higher seasonal variation levels in China’s Southeast and Southwest regions (Figure 4(a)). Notably, the extended peak of ST occurs from May to October every year in southern China.^38,77

Figure 4. Analysis of seasonal characteristics of ST the three endemic region (Southeast, Southwest and central East China between 2006 and 2018 based on data reported by (Xin et al. 2019).⁷⁷

While ST is known to occur in several areas of China,^8,97 data have indicated a dramatic increase in the number of cases across the country (Figure 5), indicating this disease is a growing health problem.^{9,38,65,81,98} Moreover, the incidence of ST is associated with an adequate temperature, and rainfall,^4,99 breeding of rodents and mites, and a combination of climate change and geographic factors, and the expansion of humans.^39,64,100 may play roles in reemergence and the occurrence of ST. Indeed, there is a need to better understand the drivers of ST outbreaks in China. This strategy will enhance the capacity for effective bio-surveillance of ST outbreaks and mitigating safeguard public health concerns. Furthermore, a clear understanding of ST status factors will be informative for future prevention and control, including developing a reliable vaccine.

Figure 5. Scrub typhus prevalence in China between 2006 and 2018 based on data reported by (Xin et al. 2019).⁷⁷

Outbreaks of ST in China

Scrub typhus outbreak was reported in many provinces and cities in China, including Liaoning, Shandong, Fujian, Zhejiang, Jiangsu, and Tianjin. Moreover, ST has been designated an emerging infectious disease in northern China.⁸⁶ The outbreak has expanded to encompass Guangdong province and the southern parts of Shandong province,⁷¹ and northern China.^9,34,37 The disease’s seasonality has led to local outbreaks of ST within Guangdong province.¹¹ Notably, ST has also become the most common vector-borne disease in southern China.^101,102 Although ST dates back from time immemorial, this disease was not classified as an important disease until the twentieth century by the Chinese CDC Report System.⁵⁷Furthermore, clinically suspected ST patients are now reported directly to the municipal center or provisional Centers for Disease Control (CDC) for registration and confirmation. In 2011, ST become highly prevalent in southwest China,⁹⁶ and the cases were reported in many others area in China.^4,5,9,70

The multiple complications associated with ST.⁹⁷ have placed a great burden on public health and the Chinese economy due to its widespread occurrence in recent years.¹⁰³ Studies conducted on the distribution of ST in China have shown that the majority of cases have occurred between June and November and are clustered in Yunnan, Guangdong, Guangxi, Fujian, and Anhui during this period. Furthermore, ST outbreaks in Guangdong and Yunnan provinces are considered the most serious.⁸⁷ Additional data have also indicated that the annual incidence rate in Southwest China increased by more than 21-fold from 2006 to 2017.¹⁰⁴

On the other hand, ST returning travelers becomes a life-threatening public health issue not only in China but also outside China,¹⁰⁵ with required public health interventions.⁵ It has been reported that people who live in urban areas of China are also traveling to the rural areas to meet with their families member or for leisure and entertainment (e.g., camping, fishing, hiking, picnicking, and picking fruit) on the weekends and holidays. Therefore, these groups susceptible to ST infection spread the infections to non-endemic areas with an increased risk of ST diseases during the frequent outdoor activities in endemic areas. Reported new cases might become a challenge for physician’s inexperience with the ST clinical.⁵⁷ Therefore, increased ST cases among the urban population. This leads to change ST epidemiological trends in China and call for an enhanced ST disease control and prevention program strategies,^38,57 for individuals who are traveling to rural areas of China during the disease endemicity and so that early treatment can be offered to those who return with the infection of ST.

Genetic diversity

Genetic studies of O. tsutsugamushi and a detailed panel of clinical and laboratory profiles of ST cases in China.^{5,6,8,106,107} have been informative for reconstructing the genetic relationships among bacteria from ST patients in recent years.^{4,38,108–112} For example, analyses of bacterial genomes has led to more information about bacterial strains in regions where ST outbreaks have occurred.^38,111–113

By using molecular biologic approaches, scientists will obtain additional information regarding key bacterial genotypes in patients, rodents, and chiggers in a specific geographic region wherever an outbreak arises. In China,¹¹⁴ many ST cases were caused by the Kawasaki bacterial strain;⁷ however, Karp, Gilliam, and Kato bacterial types have started to appear in recent years. To date, ST outbreaks caused by the Kawasaki strain have been reported in Jiangsu and Shandong provinces,^110,114,115 while the Gilliam, Kato, and Karp strains have been observed mainly in Henan Province.¹⁰⁸ Interestingly, the Kawasaki bacterial types’ genetic profile in a patient from Jiangsu province is similar to the genetic profiles of the strain found in domestic rodents and other host species in Shandong province.^5,116 The Gilliam strain was reported in Anhui, located in eastern China;¹¹ whereas, the Karp, Kato, Gilliam, and TA763 strains were detected in the Guangdong province located in the southern part of China.^6,8

Although ST is considered a life-threatening disease,¹¹⁷ it is still highly neglected and is becoming an important public health issue in China^5,8 partly due to its broad geographical distribution, large number of confirmed cases,^118,119 and the level of genetic diversity of the causative pathogen.^{11,38,110,115} More detailed molecular studies are needed to development of prevention and control strategies.^5,8 In particular, the analysis of O. tsutsugamushi genotypes and a better understanding of the pathogen’s geographic diversity could provide new information that could contribute to the fight against ST.^3,116

Management of ST

Deviation from the disease’s normal clinical manifestations makes it more challenging to accurately diagnose ST, which can delay treatment and lead to more serious complications.⁸⁹ Thus, timely diagnosis can improve the success rate of treatment. To our knowledge, there is currently no vaccine available that will prevent and/or control infection by O. tsutsugamushi. This reality may be due to the enormous antigenic variation on the cell surface of O. tsutsugamushi strains.¹²⁰

Major antibiotics, known to be effective against O. tsutsugamushi, include tetracycline, doxycycline, azithromycin, and rifampicin. Among these antibiotics, rifampicin should be considered as the second line treatment option, since its usage can induce resistance to Mycobacterium tuberculosis.¹²¹ Furthermore, antimicrobial therapy with doxycycline or azithromycin has been used to treat severe complications, such as gastrointestinal bleeding and cholecystitis, in ST patients, but this treatment course might not be appropriate in all cases.¹²²

Additionally, the failure of clinicians in a primary health care setting to recognize ST as an underlying cause of severe symptoms may lead to the delay in appropriate treatment, increasing the rate of morbidity and mortality among ST positive patients.^123–125

While the ST is a bacterial disease, an antibiotics (chloramphenicol, tetracycline, and doxycycline) have been used to treat the disease.^121,125,126 However, resistance to these antibiotics has been report^120,126-128 followed by multiple failures and deaths associated with their use.¹²⁹ Moreover, antibiotics have become a major global health care problem; in particular, antibiotic resistance can develop.¹³⁰ Indeed, the continuous use of different antibiotics to treat ST can lead to the simultaneous development of multidrug-resistant (MDR) bacterial strains.^{27,29,131–133} Moreover, doxycycline resistance is argued to have contributed in increased cases’s of ST.^127,134,135 Therefore, antibiotic resistance of ST has led to considerations for the improvement of treatment protocols and the need for enhanced public health awareness.⁷⁵ Lastly, several proteins of O. tsutsugamushi that fall under the category of transporters, enzymes, DNA‐binding, secretory, and outer membrane proteins have been evaluated for their potential use as therapeutic agents that can target their metabolic pathways. To date, about 46 likely proteins essential for the survival of O. tsutsugamushi have been identified as therapeutic targets.¹³²

Conclusion and future vaccine developemts

Scrub typhus is one of the oldest and pernicious diseases in humans. However, the disease is still widely misdiagnosed by local clinicians in settings (e.g. rural regions) where this disease’s public health burden prevails. Therefore, health education programs should be carried out in outbreak zones to raise people’s awareness about the cause, routes of transmission and symptoms of ST. Furthermore, improved prevention and control methods, such as rapid and accurate surveillance followed by a molecular diagnostic test for individuals in affected regions in China, should be implemented. Early diagnosis is also critical for preventing the risk of severe complications and death arising from infection. Indeed, the use of molecular and serological techniques will further strengthen clinicians’ ability to diagnose ST during the initial phase of the illness. Antimicrobial therapy using doxycycline or azithromycin antibiotics in febrile patients before a diagnosis can reduce the morbidity and mortality associated with the disease. However, given the potential for antibiotic resistance, further research should focus on developing new therapeutic agents.

However, over the last 70 years, the development of an effective prophylactic vaccine against ST has been pursued. For example, a novel recombinant antigen derived from a major outer membrane protein was evaluated for its usefulness as a protective vaccine component; results indicate that this recombinant antigen can potentially play a beneficial role in combatting a wide range of O. tsutsugamushi strains.¹³⁶ In addition, Salmonella-derived extracellular vesicles containing full-length DNA sequences coding for several O. tsutsugamushi proteins were evaluated for their ability to induce T-cell immunity. It is believed that this new vaccine platform can be utilized to maximize T-cell response against O. tsutsugamushi.¹³⁷ However, despite continuous efforts to develop effective vaccines, this objective remains unfulfilled.^32,138

The changing epidemiology of ST in China warrants an enhanced disease control and prevention program. Therefore,³⁸ with absent of vaccine ST, has been become one of the neglected diseases with an emerging and reemerging disease in many provinces in China.¹⁰⁴ There is an emphasis on the need to develop a successful ST vaccine for people in endemic areas and the world where more than one million ST cases occur each year. The fact that the different strains of O. tsutsugamushi were a broad wide challenge for future ST vaccine development where the scientific research community should focus on identifying proper immunodominant antigens or combinations, which would bring about long term broad-based protection against ST infection.³²

To date, there is still no effective and reliable human vaccine against ST and no point-of-care diagnostics available.⁹⁰ However, there is no licensed human vaccine to prevent ST infection. Therefore, attention should be paid to ST in mainland China, and effective prevention and control should be taken toward future directions of ST vaccine development. Besides the continuous surveillance of the changing process of epidemiological features and investigation on the pathogenic characteristics of ST are essential for vaccine development and prevention of the disease in China.¹³⁹

For example, vaccines based on antigens derived from a major outer membrane protein need to be further evaluated to determine its efficacy so that in the coming years they will be commercially available. Such vaccines, if commercialized, will become the backbone of ST prevention all over the world.

Author’s contributions

THM, TA, WL, MNW,KS: Study conception and designed, and data acquisition, and interpreted the data and wrote the first darft of the paper. HHM,RT D, WC,MCC, PW reviewed and editing. All the authors approved the final version for publication.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Additional information

Funding

This study was funded by a grant from the Jiangsu Provisional Social Sciences Foundation Grant number [13TYA001].