Abattoir-associated Q fever: a Q fever outbreak during a Q fever vaccination program

OBJECTIVES: To investigate an abattoir outbreak of Q fever in southem New South Wales with reference to the protective effect and safety of the formalin-inactivated Q fever vaccine (Q Vax) administered before and during the outbreak. METHODS: In September 1998, after notification of four Q fever cases in the abattoir, a cohort investigation of 103 workers was undertaken. Data on age, sex, immune status, vaccination status and main work area were obtained from the medical officer administering the vaccination program and abattoir records. Symptoms and occupational risk factors for illness were obtained from interview of 63 (61%) employees. RESULTS: Of 103 abattoir employees, 16 (16%) had immunity from previous Q fever exposure and 19 (18 %) had been vaccinated at least six weeks before the first case of Q fever exposure in the abattoir. Of the remaining 68 workers who were susceptible to primary infection, 29 (43%) had laboratory confirmed acute primary Q fever and eight were suspected cases. No workers vaccinated before the likely period of exposure developed Q fever. Of 32 workers vaccinated post-exposure, four developed laboratory-confirmed Q fever within eight days of vaccination. Vaccination administered 10 or more days after the likely period of exposure showed no significant protective effect (RR=0.57; 95% CI 0.13-2.57; p=0.60). CONCLUSIONS: Q-Vax was highly effective when administered in advance of the likely period of Q fever exposure. Post exposure vaccination was not shown to be protective. IMPLICATIONS: This study reinforces meat industry vaccination guidelines for abattoir employees. The optimal time to vaccinate workers is before they are put at occupational risk.     

A randomized, controlled, double-blind, cross-over, clinical trial of Q fever vaccine in selected Queensland abattoirs

A limited, randomized, blind, placebo-controlled trial of Q fever and influenza vaccines has been conducted in three Queensland abattoirs on a sequential analysis design. Ninety-eight subjects were given Q fever vaccine and 102 influenza vaccine. Q fever cases were observed in unvaccinated workers in all three abattoirs during the period of observation. A total of seven Q fever cases in one group, one more than the number required to achieve statistical significance between the two vaccine groups, was reached after 15 months with the cases coming from two of the abattoirs. These Q fever cases were in the group which had been given influenza vaccine and none in that given Q fever vaccine. Symptomless seroconversion rates of 24% were found in the remaining influenza virus vaccinees, and those without immunity were given Q fever vaccine.     

Control strategies for Q fever based on results of pre-vaccination screening in Victoria, 1988 to 2001

OBJECTIVE: Data from Q fever pre-vaccination screening were analysed to determine the level of agreement between the two tests of immunity and between disease or vaccination history and immunity, trends in proportion of participants immune to Q fever, and the annual risk of infection. METHOD: Data from nearly 10,000 screening episodes between July 1988 and June 2001 on Victorian workers at high risk were assessed. RESULTS: Most participants were male (86%) and employed in Victorian abattoirs (81%). Agreement between results of tests for immunity was 'fair' (kappa=0.52). Self-reported history of vaccination or infection was a poor predictor of immunity. The proportion of positive blood and skin tests increased with years of exposure to animals/meat, but decreased over the 13-year period with shorter exposures. Hence the percentage requiring vaccination increased from 50% in 1998 to 90% in 2001. The average annual risk of infection among abattoir workers was 45.0 per 1,000 (95% CI 42.3-47.6), and 62.6 per 1,000 (95% CI 57.5-67.7) over the first 10 years of exposure. CONCLUSIONS: This is the first Australian study to estimate the annual risk of Q fever infection in abattoir workers. The study confirmed previous findings of poor agreement between screening tests and predictive value of history of vaccination/ exposure. Up to 90% of new entrants in high-risk workplaces will be susceptible to Q fever and require vaccination. IMPLICATIONS: Systematic post-marketing surveillance is needed to monitor adverse events to the vaccine, duration of protection and possible reasons for vaccine failures.     

Comparative efficacy and immunogenicity of Q fever chloroform:methanol residue (CMR) and phase I cellular (Q-Vax) vaccines in cynomolgus monkeys challenged by aerosol

Preliminary evidence gathered in rodents and livestock suggested that a phase I chloroform:methanol residue (CMR) extracted vaccine was safe and efficacious in protecting these animals from challenge with the obligate phagolysosomal pathogen (Coxiella burnetii). Prior to the initiation of phase II studies in human volunteers, we compared, in non-human primates (Macaca fascicularis), the efficacy of CMR vaccine with Q-Vax, a licensed cellular Australian Q fever vaccine that has been demonstrated to provide complete protection in human volunteers. Vaccine efficacy was assessed by evaluating thoracic radiographs and the presence of fever and bacteremia in monkeys challenged by aerosol with Coxiella burnetii. Changes in blood chemistries, hematology, behavior and pulmonary function were also examined. CMR, whether administered in single 30 or 100 microg doses or two 30 microg subcutaneous doses, gave equivalent protection in vaccine recipients as a single 30 microg dose of Q-Vax. In addition, vaccination resulted in significant, although temporary, increases in specific antibody titers against C. burnetii phases I and II antigens. The C. burnetii CMR vaccine may be an efficacious alternative to cellular Q fever vaccines in humans.     

Q fever vaccine efficacy and occupational exposure risk in Queensland,Australia: A retrospective cohort study

Q-VAX® is a vaccine used to prevent Q fever. Administration of the vaccine is complicated by the need to ensure, using intradermal and serological tests, that individuals have no prior immunity. Previous studies suggest that the vaccine is highly efficacious and long-lasting in adults. However, there has been no systematic follow-up of vaccine efficacy and the longevity of immunity using population-level data. We aimed to investigate the vaccine failure rate and duration of immunity in previously vaccinated individuals. We formulated a retrospective cohort study design within a linked data. We used a Q fever vaccination registry linked to Q fever notifications and hospital admissions (1991–2016) in the state of Queensland, which has Australia’s highest incidence of Q fever. Q-VAX® failure was defined as occurrence of Q fever > 14 days’ after vaccination. The incidence of Q fever in vaccinated and unvaccinated individuals was 5.40 (95% CI: 3.65, 7.72) and 89.50 (95% CI: 70.50, 112.00]) per 100,000 person-years of follow-up, respectively. The hazard ratio (HR) for Q fever was 0.07 (95% CI: 0.04, 0.10) in non-immune vaccinated compared with immune unvaccinated individuals. The overall vaccine effectiveness was found to be 94.37% suggesting that Q-VAX® is highly effective at preventing Q fever. However, the greater incidence observed in unvaccinated individuals considered immune during the pre-vaccination screening may suggest that pre-vaccination screening is sub-optimal among this study population.     

Long-term immunogenicity of hepatitis B vaccination in a cohort of Italian healthy adolescents

In 1992, 620 adolescents were vaccinated against hepatitis B. Anti-HBs concentrations were measured in 480 (77.4%) adolescents 1 month after completion of the primary course of vaccination. To assess the persistence of anti-HBs, 347 and 228 of such vaccinees were retested for anti-HBs in 1999 and for anti-HBs and anti-HBc in 2003. More than 10 years after vaccination, individuals with anti-HBs >or=10 mIU/ml were considered protected while those with antibody <10 mIU/ml were given a booster dose and retested 2 weeks later. Check performed in 2003 showed that 208/228 (91.2%) vaccinees retained protective concentrations of anti-HBs. All vaccinees were anti-HBc negative. 11 of the 12 (91.7%) individuals who were given a booster dose of vaccine showed a vigorous anamnestic response while the remaining one showed a weak response (10.6 mIU/ml). These data suggests that hepatitis B vaccination can confer long-term immunity and that immunological memory can outlast the loss of antibody. Hence, the use of routine booster doses of vaccine does not appear necessary to maintain long-term protection in successfully vaccinated immunocompetent individuals.     

Effect of vaccination with phase I and phase II Coxiella burnetii vaccines in pregnant goats

Livestock is considered to be the major "source" of human Q fever. The efficacy of two currently available vaccines (Coxevac, phase I, CEVA Santé Animale and Chlamyvax FQ, phase II, MERIAL) against Coxiella excretion was investigated in terms of risks to human health. Two months before mating, 17 goats were vaccinated subcutaneously against Coxiella burnetii with an inactivated phase I vaccine and 16 goats were vaccinated with an inactivated phase II Coxiella mixed with Chlamydophila abortus vaccine. Fourteen goats were left unvaccinated. At 84 days of gestation, the goats were subcutaneously challenged with 10(4) bacteria of C. burnetii strain CbC1. Phase I vaccine was effective and dramatically reduced both abortion and excretion of bacteria in the milk, vaginal mucus and feces. In contrast, the phase II vaccine did not affect the course of the disease or excretion.     

Distribution of immunoglobulin G (IgG) and A (IgA) subclasses following Q fever vaccination with soluble phase I Coxiella burnetii extract

High levels of IgG1, IgG3 and IgA2 antibodies have been observed in patients with Q fever following Coxiella burnetii infection. This IgG subclass distribution is more typical of viral and autoimmune diseases than of bacterial infections. It seemed, therefore, of interest to carry out a prospective study of the distribution of immunoglobulin subclasses after vaccination with phase I C. burnetii tricloroacetic soluble extracts to detect possible differences with respect to natural infection. The antibody response found in vaccinees was mainly restricted to the IgG1, IgG2 and IgA1 subclasses. These findings confirm differences in isotype distribution when compared to those of patients with acute or chronic Coxiella infections and opens an area of interest with respect to the role of IgA subclasses.     

Q-Vax Q fever vaccine failures,Victoria, Australia 1994–2013

Q-Vax®, a whole cell formalin inactivated vaccine, is currently the only licensed Q fever vaccine for humans world-wide. Efficacy is high, although vaccine failures have been described for those vaccinated within the incubation of a naturally acquired infection. In Australia, it is widely used to prevent occupational acquisition of Q fever and is the mainstay for outbreak control. A retrospective review of all notified cases of acute Q fever to the Victorian department of health, 1993–2013, revealed 34 of 659 cases were previously vaccinated and 10 cases were positive on pre-vaccination screening, precluding vaccination. Twenty-one cases described high-risk exposures for C. burnetii prior to and within 15 days post vaccination and are likely to have been vaccinated within the incubation period of a natural infection. Thirteen cases described symptom onset more than 15 days post vaccination and thus may represent the first described series of Q-Vax vaccine failures following appropriate vaccination.     

Reduction of Coxiella burnetii prevalence by vaccination of goats and sheep, The Netherlands

Recently, the number of human Q fever cases in the Netherlands increased dramatically. In response to this increase, dairy goats and dairy sheep were vaccinated against Coxiella burnetii. All pregnant dairy goats and dairy sheep in herds positive for Q fever were culled. We identified the effect of vaccination on bacterial shedding by small ruminants. On the day of culling, samples of uterine fluid, vaginal mucus, and milk were obtained from 957 pregnant animals in 13 herds. Prevalence and bacterial load were reduced in vaccinated animals compared with unvaccinated animals. These effects were most pronounced in animals during their first pregnancy. Results indicate that vaccination may reduce bacterial load in the environment and human exposure to C. burnetii.     

Immunisation with purified Coxiella burnetii phase I lipopolysaccharide confers partial protection in mice independently of co-administered adenovirus vectored vaccines

Q fever is a highly infectious zoonosis caused by the Gram-negative bacterium Coxiella burnetii. The worldwide distribution of Q fever suggests a need for vaccines that are more efficacious, affordable, and does not induce severe adverse reactions in vaccine recipients with pre-existing immunity against Q fever. Potential Q fever vaccine antigens include lipopolysaccharide (LPS) and several C. burnetii surface proteins. Antibodies elicited by purified C. burnetii lipopolysaccharide (LPS) correlate with protection against Q fever, while antigens encoded by adenoviral vectored vaccines can induce cellular immune responses which aid clearing of intracellular pathogens. In the present study, the immunogenicity and the protection induced by adenoviral vectored constructs formulated with the addition of LPS were assessed. Multiple vaccine constructs encoding single or fusion antigens from C. burnetii were synthesised. The adenoviral vectored vaccine constructs alone elicited strong cellular immunity, but this response was not correlative with protection in mice. However, vaccination with LPS was significantly associated with lower weight loss post-bacterial challenge independent of co-administration with adenoviral vaccine constructs, supporting further vaccine development based on LPS.     

Subcutaneous inoculation of a whole virus particle vaccine prepared from a non-pathogenic virus library induces protective immunity against H7N7 highly pathogenic avian influenza virus in cynomolgus macaques

Development of H7N7 highly pathogenic avian influenza virus (HPAIV) vaccines is an urgent issue since human cases of infection with this subtype virus have been reported and most humans have no immunity against H7N7 viruses. We made an H7N7 vaccine combining components from an influenza virus library of non-pathogenic type A influenza viruses. Antibody and T cell recall responses specific against the vaccine strain were elicited by subcutaneous inoculation with the whole virus particle vaccine with or without alum as an adjuvant in cynomolgus macaques. No significant difference was observed in magnitude of antibody responses between vaccination with alum and vaccination without alum, though vaccination with alum induced longer recall responses of CD8⁺ T cells than did vaccination without alum. After challenge with a subtype of H7N7 HPAIV, the virus was detected in nasal swabs of unvaccinated macaques for 8 days but only for 1 day in the animals vaccinated either with or without alum, although the macaques vaccinated with alum showed elevated body temperature more briefly after infection. These findings demonstrated that this H7N7 HPAIV strain is pathogenic to macaques and that the vaccine conferred protective immunity to macaques against H7N7 HPAIV infection.     

Freeze-dried live attenuated smallpox vaccine prepared in cell culture “LC16-KAKETSUKEN”: Post-marketing surveillance study on safety and efficacy compliant with Good Clinical Practice

BackgroundIn Japan, production of smallpox vaccine LC16m8 (named LC16-KAKETSUKEN) was restarted and was determined to be maintained as a national stockpile in March 2002.ObjectiveTo conduct a post-marketing surveillance study of the vaccination of freeze-dried live attenuated smallpox vaccine prepared in cell culture LC16-KAKETSUKEN using attenuated vaccinia strain LC16m8. The study complied with Good Clinical Practice, focusing on a comparison between primary vaccinees and re-vaccinees.Method268 personnel (261 males and 7 females) of the Japan Ground Self-Defense Force were inoculated with LC16-KAKETSUKEN and thereafter adverse events and efficacy were evaluated.ResultsAmong 268 vaccinee participants, the following vaccinees showed adverse events, none serious: 53 of 196 primary vaccinees (without previous smallpox vaccination), 4 of 71 re-vaccinees (with previous smallpox vaccination) and 1 vaccinee with unknown previous vaccination history. A breakdown of adverse events observed in this study (total 268 vaccinees) showed the following minor or mild adverse events: 52 (19.4%) swelling of axillary lymph node, 4 (1.5%) fever, 2 (0.7%) fatigue, 1 (0.4%) of rash, 14 (5.2%) erythema at the inoculation site, 1 (0.4%) swelling at the inoculation site and 1 (0.4%) autoinoculation. The incidence of adverse events for primary vaccinees (53/196; 27.0%) was significantly higher than for re-vaccinees (4/71; 5.6%). However, the proportion of vaccine take was significantly higher for primary vaccinees (185/196; 94.4%) than for re-vaccinees (58/71; 81.7%). Although the proportion of vaccine take of re-vaccinees was significantly lower than for primary vaccinees due to preexisting immunity by previous vaccination, no significant difference was found in neutralizing antibody titers between primary vaccinees and re-vaccinees at 1, 4 and 7 months after LC16-KAKETSUKEN vaccination.ConclusionThe present post-marketing surveillance study compliant with Good Clinical Practice demonstrated the efficacy and safety of the smallpox vaccine LC16-KAKETSUKEN in an adult population. LC16-KAKETSUKEN is the sole currently available licensed smallpox vaccine for both adult and pediatric populations.     

Effect of low level immunity on response to live rubella virus vaccine

Serum specimens of 1075 young adults representing nursing and medical staff were collected for determination of rubella immunity using the radial haemolysis (RH) technique, also known as the haemolysis in gel (HIG) test. Of the sera 84 (7.8%) were negative (RH titre <4 mm) and an additional 93 (8.7%) gave an RH titre of 4–5 mm, which was regarded as the limit of immunity. Initially, 64 persons of these 177 were vaccinated with the RA27/3 strain of live attenuated rubella virus. Their serum samples were collected at the time of vaccination and at three weeks and three months after vaccination. Altogether 54 vaccinees could be followed for their immune response throughout the study. It became obvious that vaccination generally caused seroconversion only after three months rather than within three weeks. Only one person remained seronegative - even after a booster dose of vaccine. The mean final antibody titres in individuals with pre-existing low level immunity was 6 mm whereas in initially seronegative persons the antibody titre after vaccination was 8.5 mm on average. Thus a pre-existing low level immunity will effectively block the immune response to live rubella virus vaccine and this phenomenon may explain some apparent vaccination failures.     

快速荧光灶抑制试验检测暴露后人群接种狂犬病疫苗的免疫学效果

目的调查暴露后人群接种狂犬病疫苗（Rabies Vaccine for Human Use,RabV）的免疫学效果。方法122例暴露后,病例接种RabV后应用快速荧光灶抑制试验检测抗体产生情况。结果3剂免疫后抗体阳性率达99．1％,5剂免疫后抗体阳性率为100％;不同性别病例抗体几何平均滴度差异无统计学意义。青少年接种RabV的应答较快,中老年接种RabV的应答较慢。结论对要确定是否需要接受RabV加强接种以建立一个可接受的暴露前免疫状态,对有免疫缺陷等身体状况特殊者,有必要检测接种RabV后的中和抗体,对未产生抗体者应及时补充免疫,确保免疫学效果。     

Cell-mediated and antibody immune responses to AIK-C and Connaught monovalent measles vaccine given to 6 month old infants

Measles vaccination of infants younger than 1 year of age should be successful in populations with a high proportion of measles vaccinated mothers. Infants whose mothers were vaccinated are born with less maternal antibody which can interfere with vaccination compared with infants whose mothers had measles. AIK-C or Connaught (CLL) measles vaccine was given to 300 6 month infants born to mothers who had measles (group 1) or who were vaccinated against measles (group 2). Pre- and post-vaccination measles antibody was measured by EIA and PRN and cell mediated immunity (CMI) by blast transformation and production of interferon-gamma and interleukin-10. After vaccination, mean antibody level, seroconversion and blastogenesis were significantly lower for group 1 than group 2 (p < 0.05). Post-vaccination measles IgG was significantly higher for group 2 CLL vaccinees compared with group 2 AIK-C (p < 0.05); seroconversion rates were 73 and 63%, respectively. More than 93% of group 2 infants had elevated measles IgG after vaccination. About 89% of all children had some evidence of a blastogenic response. Lymphoproliferation correlated strongly with cytokine production and weakly with IgG. Not all seroresponders had a CMI response and vice versa. AIK-C and CLL vaccines induce strong measles specific T and B immunity in most 6 month infants of vaccinated mothers.     

海拉尔铁路工务系统职工接种森林脑炎疫苗免疫效果观察

目的为了解海拉尔铁路工务系统的线路工人接种森林脑炎疫苗后的免疫效果。方法随机抽取工务系统在林业区段作业的402名职工,于预防接种前和接种后三周进行静脉采血,采用酶联免疫法进行抗体检测。结果免疫接种后抗体阳性率为98.76%;免疫前连续接种5年者抗体阳性率高于连续接种3年者、未连续接种者和从未接种者;吸烟、饮酒等不良生活习惯并不影响注射疫苗后抗体的产生。结论长春生物制品研究所研制的这种新型地鼠肾纯化灭活疫苗（森泰保）具有较高的抗体阳转率,但接种疫苗后的抗体水平维持时间较短,需每年进行加强注射才能维持身体内的抗体水平。接种年限越长血清抗体水平越高。吸烟、饮酒不良生活习惯不影响抗体的产生。     

Rift Valley fever virus vaccine trial: study of neutralizing antibody response in humans

The serological response to immunization with a formalin inactivated Rift Valley fever (RVF) vaccine was studied in 963 Swedish UN soldiers serving in the Sinai peninsula. Antibody titres were determined with a plaque reduction neutralization test (PRNT). Attempts were made to give all soldiers three injections (1 ml s.c. days 0, 7-10 and 28-30) but 128 soldiers received only two injections. In a group of 51 fully vaccinated individuals, repeated blood samples were collected. Fifty of the vaccinees seroconverted. Serum collected six weeks after the first vaccination revealed the highest antibody titres. The geometric mean titre then decreased rapidly during the following two weeks. Six months after vaccination sera were collected from 433 vaccinees who had received three injections and 379 had antibodies detectable by PRNT (88% PRNT greater than or equal to 10). The corresponding figures one and two years after vaccination were 223 seropositives out of 255 (91% PRNT greater than or equal to 10) and 91 out of 123 (74% PRNT greater than or equal to 10), respectively. Multiple stepwise regression showed that three injections gave a better antibody response than two injections. This analysis also showed that the magnitude of the antibody response was reduced with increasing age. Slight, local and general side effects were reported in 6% of the vaccinees and these reactions occurred in individuals with relatively higher antibody response.     

Safety profile and immunogenicity of an inactivated vaccine derived from an attenuated strain of hepatitis A.

To determine the safety and immunogenicity of an inactivated hepatitis A vaccine, 56 healthy adult volunteers were randomly assigned to receive an intramuscular injection of 6.3, 12.5 or 25 ng of inactivated hepatitis A vaccine or placebo at 0, 2 or 4, and 24 weeks. Adverse reactions occurred with similar frequency in vaccine and placebo recipients and consisted primarily of pain or tenderness at the injection site. By 4 weeks after a single 6.3, 12.5 or 25 ng injection, seven, nine and ten out of ten vaccinees, respectively, had antibody detectable by a HAV AB assay modified to increase its sensitivity tenfold. All vaccinees had antibodies detectable by this assay within 2 weeks of their second inoculation. Geometric mean antibody levels increased with higher doses of vaccine (p = 0.05). Neutralizing antibody was detected within 4 weeks of a single inoculation in all vaccinees. Neutralizing antibody was detected after the third inoculation at dilutions of greater than or equal to 1:2048 in all 12.5 and 25 ng vaccinees. All 19 vaccinees tested at 24 months still had HAV antibodies detectable by a modified HAV AB assay. This inactivated hepatitis A vaccine appears to be well tolerated and immunogenic at doses of 6.3-25 ng. The choice of dose and vaccination schedule may depend on the rapidity with which seroconversion is desired.     

惠州市1186例狂犬病疫苗接种者免疫效果分析

目的分析惠州市人狂犬病疫苗暴露后免疫的抗体水平,及时了解和观察本市犬咬伤人群接种狂犬病疫苗后（IgG）抗体产生的免疫效果,评价目前本市使用的狂犬病疫苗质量,为今后的狂犬病疫苗预防接种工作及制订科学完善的防患措施提供科学依据。方法惠州市人狂犬病疫苗暴露后（咬伤后）,抽取全程接种五针疫苗1个月后自愿进行狂犬病毒抗体检测人员静脉血,按酶联免疫法检测抗狂犬病毒抗体。结果惠州市1186例接种狂犬疫苗后抗狂犬病毒抗体水平检测阳性率为96.1%。其中男性97.2%,女性94.5%。不同年龄组抗狂犬病毒抗体阳性率有随着年龄的增长而呈下降的趋势。不同厂家狂犬疫苗免疫效果相当,差异无统计学意义。结论通过0、3、7、14和28d全程接种狂犬疫苗后,96.1%以上的患者抗狂犬病毒抗体水平合格,还有3.9%的患者抗体水平低于保护阈值,需进一步加强接种。