Protective Immunity against SARS Subunit Vaccine Candidates Based on Spike Protein: Lessons for Coronavirus Vaccine Development.

The recent outbreak of the novel coronavirus disease, COVID-19, has highlighted the threat that highly pathogenic coronaviruses have on global health security and the imminent need to design an effective vaccine for prevention purposes. Although several attempts have been made to develop vaccines against human coronavirus infections since the emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003, there is no available licensed vaccine yet. A better understanding of previous coronavirus vaccine studies may help to design a vaccine for the newly emerged virus, SARS-CoV-2, that may also cover other pathogenic coronaviruses as a potentially universal vaccine. In general, coronavirus spike protein is the major antigen for the vaccine design as it can induce neutralizing antibodies and protective immunity. By considering the high genetic similarity between SARS-CoV and SARS-CoV-2, here, protective immunity against SARS-CoV spike subunit vaccine candidates in animal models has been reviewed to gain advances that can facilitate coronavirus vaccine development in the near future.

Roadmap to developing a recombinant coronavirus S protein receptor-binding domain vaccine for severe acute respiratory syndrome.

A subunit vaccine, RBD-S, is under development to prevent severe acute respiratory syndrome (SARS) caused by SARS coronavirus (SARS-CoV), which is classified by the US NIH as a category C pathogen. This vaccine is comprised of a recombinant receptor-binding domain (RBD) of the SARS-CoV spike (S) protein and formulated on alum, together with a synthetic glucopyranosyl lipid A. The vaccine would induce neutralizing antibodies without causing Th2-type immunopathology. Vaccine development is being led by the nonprofit product development partnership; Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development in collaboration with two academic partners (the New York Blood Center and University of Texas Medical Branch); an industrial partner (Immune Design Corporation); and Walter Reed Army Institute of Research. A roadmap for the product development of the RBD-S SARS vaccine is outlined with a goal to manufacture the vaccine for clinical testing within the next 5 years.

Uniformed service nurses' experiences with the severe acute respiratory syndrome outbreak and response in Taiwan.

Severe Acute Respiratory Syndrome (SARS) had an enormous effect on Taiwan's public health and the nation's economy. To prevent the spread of the epidemic, the government implemented strategies and measures for the control of the epidemic. The Ministry of National Defense also fully supported epidemic prevention by mobilizing all necessary human and material resources. Under the plan executed by the Ministry of National Defense, the SongShan Armed Forces Hospital became Taiwan's first hospital dedicated exclusively for the treatment of patients with SARS. Uniformed Service Nurses' devoted to caring for patients with SARS during the outbreak made significant contributions to the prevention and control of SARS.

Protein transfer enhances cellular immune responses to DNA vaccination against SARS-CoV.

The current DNA vaccine formulations are not optimal for stimulation of CD8(+) T cells, which are required for clearing virally-infected cells. Here we show that CD8(+) T cell-stimulating activity can be effectively augmented by combining DNA vaccination with protein transfer. C57BL/6 mice were injected intramuscularly with an anti-SARS-CoV DNA vaccine admixed with a lipid-derived conjugate of 4-1BBL, a potential CD8(+) T-cell co-stimulator. The inclusion of the lipidated co-stimulator greatly enhanced cellular immune responses, especially the CTL response, induced by the DNA vaccine. The adjuvant effect of 4-1BBL was lipidation-dependent, indicating that it functions as a cell membrane-anchored co-stimulator. Results of our study suggest, for the first time, that muscle cells may be modified in situ, at the DNA injection site, into APC-like cells to allow direct priming of CD8(+) T cells and thereby improve the efficacy of DNA vaccines.

Pandemic flu: lessons from the Toronto SARS outbreak.

A review of the severe acute respiratory syndrome outbreak in Ontario in 2003 found that there had been several faults in healthcare services and that these had contributed to the spread of infection and the deaths of two nurses. This article argues that, six years on, these faults have not been rectified and that Ontario healthcare services may be unprepared for an H1N1 outbreak. The assistant deputy public health minister of Toronto offers her response.

The antiviral action of common household disinfectants and antiseptics against murine hepatitis virus, a potential surrogate for SARS coronavirus.

BACKGROUND: The 2003 outbreak of severe acute respiratory syndrome (SARS) infected over 8000 people and killed 774. Transmission of SARS occurred through direct and indirect contact and large droplet nuclei. The World Health Organization recommended the use of household disinfectants, which have not been previously tested against SARS coronavirus (SARS-CoV), to disinfect potentially contaminated environmental surfaces. There is a need for a surrogate test system given the limited availability of the SARS-CoV for testing and biosafety requirements necessary to safely handle it. In this study, the antiviral activity of standard household products was assayed against murine hepatitis virus (MHV), as a potential surrogate for SARS-CoV. METHODS: A surface test method, which involves drying an amount of virus on a surface and then applying the product for a specific contact time, was used to determine the virucidal activity. The virus titers and log reductions were determined by the Reed and Muench tissue culture infective dose (TCID)50 end point method. RESULTS: When tested as directed, common household disinfectants or antiseptics, containing either 0.050% of triclosan, 0.12% of PCMX, 0.21% of sodium hypochlorite, 0.23% of pine oil, or 0.10% of a quaternary compound with 79% of ethanol, demonstrated a 3-log reduction or better against MHV without any virus recovered in a 30-second contact time. CONCLUSION: Common household disinfectants and antiseptics were effective at inactivating MHV, a possible surrogate for SARS-CoV, from surfaces when used as directed. In an outbreak caused by novel agents, it is important to know the effectiveness of disinfectants and antiseptics to prevent or reduce the possibility of human-to-human transmission via surfaces.

Anticomplementary principles of a Chinese multiherb remedy for the treatment and prevention of SARS.

AIM OF THE STUDY: To elucidate the anticomplementary principles of a Chinese multiherb remedy used for the treatment and prevention of SARS, which contains five ingredients of Herba Houttuyniae, Flos Chrysanthemi Indici, Herba Artemisiae Scopariae, Herba Eupatorii and Fructus Tsaoko. MATERIALS AND METHODS: The anticomplementary activity was evaluated from hemolytic assays through the classical pathway (CP) and the alternative pathway (AP) of complement system in vitro. Compounds were isolated using bioactivity-guided fractionation and tested in vitro for their complement-inhibiting properties on the CP and AP. HPLC-DAD-ESI-MS was used to assign the isolated compounds in the five ingredient herbs. RESULTS: 15 compounds, including chlorogenic acid (1), rutin (2), hyperoside (3), p-hydroxyacephenone (4), scopoletin (5), quercitrin (6) (3R,4R,6S)-3,6-dihydroxy-1-menthene (7), acaciin (8), scoparone (9), luteolin (10), quercetin (11), apigenin (12), acacetin (13), aristolactam (14), and apigenin-7,4'-dimethyl ether (15) were isolated and identified. Nine flavonoids (2, 3, 6, 8, 10-13, 15) were found to show inhibitory effects towards the CP and AP of complement system, luteolin (10) was the most potent with the CH50 and AP50 values of 0.19 and 0.17 mM. The bioactive flavonoids were mainly derived from Herba Houttuyniae, Flos Chrysanthemi Indici and Herba Artemisiae Scopariae. CONCLUSIONS: A Chinese multiherb remedy used for the treatment and prevention of SARS has robust inhibitory effect on complement system through the CP and AP, and its anticomplementary activity could be attributed to the flavonoids present in some ingredient herbs. Luteolin could be a potential anticomplementary agent.

Responses of Chinese elderly to the threat of severe acute respiratory syndrome (SARS) in a Canadian community.

OBJECTIVE: To describe responses of Chinese elderly living in Edmonton, Canada, during the severe acute respiratory syndrome (SARS) pandemic, and their use of Western and/or traditional Chinese medicine. DESIGN: A QUAL-qual mixed method design, using grounded theory as the core method and ethnographic strategies are used to inform the cultural aspects of the study. SAMPLE: A purposeful sample of 19 Chinese elderly was interviewed and tape recorded. Four traditional Chinese Practitioners were also interviewed. METHODS: The interviews were transcribed and analyzed in Chinese and later translated into English. Data analysis utilized the constant comparison method. RESULTS: Participants experienced a 5-stage process of protecting self, family, and others, responding according to the perceived threat of SARS. Participants used both Western and traditional Chinese strategies to combat SARS. Their desire to protect others took precedence under the moral code of filial piety. Once SARS was under control, the community remained vigilant and continued to monitor for its possible reoccurrence. CONCLUSIONS: Cultural beliefs and practices within the Chinese population support the recommendations set by the health department for the protection of individuals and the community during the SARS pandemic. Therefore, the public health sector should become familiar with and support these Chinese cultural networks during pandemics.

SARS and health worker safety: lessons for influenza pandemic planning and response.

The outbreak of severe acute respiratory syndrome (SARS) in 2003 provided valuable lessons for protecting health workers during an influenza pandemic or other public health crisis. In its final report, the SARS Commission concluded that a key lesson in worker safety was the precautionary principle. It stated that reasonable actions to reduce risk should not await scientific certainty. As recommended by the SARS Commission, this principle has now been enshrined in the Health Protection and Promotion Act (2007), Ontario's public health legislation and in Ontario's influenza pandemic plan. Another vital lesson for worker safety involves the occupational hygiene concept of a hierarchy of controls. It takes a holistic approach to worker safety, addressing each hazard through control at the source of the hazard, along the path between the worker and the hazard and, lastly, at the worker. Absent such an approach, the SARS Commission said worker safety may focus solely on a particular piece of personal protective equipment, such as an N95 respirator (important as it may be), or on specific policies and procedures, such as fit testing the N95 respirator to the wearer (significant as it may be). In worker safety, said the commission, the integrated whole is greater than the uncoordinated parts. The third and final worker safety lesson of SARS is the importance of having a robust safety culture in the workplace in which workers play an integral role in promoting a safe workplace.

Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus.

Two different severe acute respiratory syndrome (SARS) vaccine strategies were evaluated for their ability to protect against live SARS coronavirus (CoV) challenge in a murine model of infection. A whole killed (inactivated by beta-propiolactone) SARS-CoV vaccine and a combination of two adenovirus-based vectors, one expressing the nucleocapsid (N) and the other expressing the spike (S) protein (collectively designated Ad S/N), were evaluated for the induction of serum neutralizing antibodies and cellular immune responses and their ability to protect against pulmonary SARS-CoV replication. The whole killed virus (WKV) vaccine given subcutaneously to 129S6/SvEv mice was more effective than the Ad S/N vaccine administered either intranasally or intramuscularly in inhibiting SARS-CoV replication in the murine respiratory tract. This protective ability of the WKV vaccine correlated with the induction of high serum neutralizing-antibody titres, but not with cellular immune responses as measured by gamma interferon secretion by mouse splenocytes. Titres of serum neutralizing antibodies induced by the Ad S/N vaccine administered intranasally or intramuscularly were significantly lower than those induced by the WKV vaccine. However, Ad S/N administered intranasally, but not intramuscularly, significantly limited SARS-CoV replication in the lungs. Among the vaccine groups, SARS-CoV-specific IgA was found only in the sera of mice immunized intranasally with Ad S/N, suggesting that mucosal immunity may play a role in protection for the intranasal Ad S/N delivery system. Finally, the sera of vaccinated mice contained antibodies to S, further suggesting a role for this protein in conferring protective immunity against SARS-CoV infection.

Group debriefing for people with chronic diseases during the SARS pandemic: Strength-Focused and Meaning-Oriented Approach for Resilience and Transformation (SMART).

This study presented preliminary results on the efficacy of a novel group debriefing model called Strength-Focused and Meaning-Oriented Approach for Resilience and Transformation (SMART). The SMART debriefing (1) aimed at boosting resilience and catalyzing transformation among persons undergoing stressful events, (2) adopted a growth-oriented and holistic approach of health promotion, and (3) employed methods drawn from various indigenous sources (e.g. Asian philosophies and Traditional Chinese Medicine). Participants (N=51) were people with chronic diseases recruited about 1 month (August 2003) after the Severe Acute Respiratory Syndrome (SARS) outbreak was eventually under control, after causing widespread panic in Hong Kong. After the one-day group debriefing, participants showed significant decrease in depression level, as measured by Brief Symptom Inventory (Derogatis & Melisaratos, 1983, Psychological Medicine, 13(3), 595-605) and changes in cognitive appraisal towards SARS. Such changes were sustained in a 1-month follow-up. Clinical implications and directions for further study were discussed.

Using herbal medicine as a means of prevention experience during the SARS crisis.

At the peak of the SARS epidemic in Hong Kong, hospital workers were under high risks of contraction of the infection. Herbal preparations had been used historically in China to treat influenza-like diseases. During the SARS outbreak, herbal preparations had been used jointly with standard modern treatment in China. As a means to protect the at-risk hospital workers, an innovative herbal formula was created and consumed by 3160 of them in two weeks. During the two weeks, symptoms and adverse effects were close monitored; 37 of them had their serum checked for immunological responses. The results showed that none of the herb consumers contracted the infection, compared to 0.4% among the non-consumers. Adverse effects had been infrequent and mild. There were hardly any influenza-like symptoms and the quality of life improved. In the group who volunteered to have their immunological state checked, significant boosting effects were found. It was concluded that there might be a good indication for using suitable herbal preparations as a means of preventing influenza-like infection. The mode of preventive effect could be treatment of the infection at its very early stage instead of producing a period of higher immunological ability, as in the case of vaccination.

SARS in Singapore: surveillance strategies in a globalising city.

Public health measures employed to fight against the spread of SARS need to be guided by biomedical knowledge as well as an understanding of the social science aspects of the disease. Using Singapore as a case study, we explore how the state constructs the disease and implements measures targeted at creating a ring of defense around the island and using surveillance to monitor and prevent its spread. While there is support, there is also resentment among some Singaporeans who complain that their right to privacy has been invaded and that over surveillance may have actually occurred. Marginalisation and discrimination have not only affected the local population but in this open economy which is striving to achieve global city status, businesses, tourism, foreign talent, foreign contract workers and foreign students studying in Singapore have also been negatively affected. While Singapore has been applauded by WHO and used as an example of quick and effective response, a holistic approach to the management of infectious disease must address the social implications of strategies that are drawn from medical knowledge alone because it impinges on the social lives of people and how people interact with each other under stressful circumstances.

The use of an herbal formula by hospital care workers during the severe acute respiratory syndrome epidemic in Hong Kong to prevent severe acute respiratory syndrome transmission, relieve influenza-related symptoms, and improve quality of life: a prospective cohort study.

OBJECTIVES: To investigate the efficacy of an herbal formula in the prevention of severe acute respiratory syndrome (SARS) transmission among health care workers. The secondary objectives are to investigate quality of life (QOL) and symptomology changes among supplement users, and to evaluate the safety of this formula. DESIGN: Controlled clinical trial. SETTINGS: Hong Kong during epidemic of SARS. SUBJECTS: Two cohorts of health care workers from 11 hospitals in Hong Kong, 1 using an herbal supplement for a 2-week period (n = 1063) and a control cohort comprising all other health care workers who did not receive the supplement (n = 36,111) were compared prospectively. INTERVENTIONS: Taking an herbal supplement for a 2-week period. OUTCOME MEASURES: SARS attack rates and changes in quality of life and influenza-like symptoms were also examined at three timepoints among herbal supplement users. RESULTS: None of the health care workers who used the supplement subsequently contracted SARS compared to 0.4% of the health care workers who did not use the supplement (p = 0.014). Improvements in influenza-like symptoms and quality of life measurements were also observed among herbal supplement users. Less than 2% reported minor adverse events. CONCLUSION: The results of this pilot study suggest that there is a good potential of using Traditional Chinese Medicine (TCM) supplements to prevent the spread of SARS.

Severe acute respiratory syndrome coronavirus nucleocapsid protein expressed by an adenovirus vector is phosphorylated and immunogenic in mice.

Severe acute respiratory syndrome coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. Thus, vaccination against SARS-CoV may represent an effective approach towards controlling SARS. The nucleocapsid (N) protein is thought to play a role in induction of cell-mediated immunity to SARS-CoV and thus it is important to characterize this protein. In the present study, an E1/partially E3-deleted, replication-defective human adenovirus 5 (Ad5) vector (Ad5-N-V) expressing the SARS-CoV N protein was constructed. The N protein, expressed in vitro by Ad5-N-V, was of the expected molecular mass of 50 kDa and was phosphorylated. Vaccination of C57BL/6 mice with Ad5-N-V generated potent SARS-CoV-specific humoral and T cell-mediated immune responses. These results show that Ad5-N-V may potentially be used as a SARS-CoV vaccine.

[Clinical observation on the preventive effect of kangdu bufei decoction on acute severe respiratory syndrome].

OBJECTIVE: To observe the preventive protection of Kangdu Bufei Decoction (KBD) on acute severe respiratory syndrome (SARS) in medical personnel of Hong Kong at the epidemic period. METHODS: At the epidemic period of SARS in Hong Kong, there were 2,601 medical staffs administered with KBD distributed by the Center. It was confirmed that 1,063 persons had taken it for successive two weeks according to the request and returned the effective questionnaire, they were regarded as the TCM group. The control group was consisted of 15,374 subjects who didn't take Chinese herbal medicine. Contents of the questionnaire including the condition of testee in terms of quality of life (QOL), changes of influenza-like symptoms and Warm disease symptoms. Serum immunological examination had been conducted in 37 of the persons in the TCM group. RESULTS: No one in the TCM group got SARS infection while in the control group, 64 (0.4%) had got. Self-control before and after treatment examination showed that significant improvement appeared in the TCM in aspects of influenza-like and Warm disease symptoms and QOL. The results of serum immunological examination showed that after administration of KBD, the immunity of organism was improved and elevated. CONCLUSION: KBD could prevent the occurrence of SARS, it is possibly realized through improving symptoms, elevating QOL and enhancing immunity of organism.

Statistical evidence for the usefulness of Chinese medicine in the treatment of SARS.

This study estimated case fatality rates in Hong Kong, Singapore and Beijing using the number of new admissions, deaths and discharges by cure. To determine the relationships between the hazard for death and that for cure, a cure--death hazard plot was developed. The daily ratios of the two hazards determine the ultimate case fatality rate. The case fatality rate was approximately 18% for Hong Kong and Singapore, while the rate for Beijing exceeded 52% until 5 May, was 16% for 5-19 May, and 4%-1% after 20 May. These results show a significant difference in the case fatality rate between Beijing and other areas, which seems to have been due to the difference in treatment methods. That is, it suggests that combining traditional Chinese medicine with Western medicine is useful in the treatment of SARS.