Modelling the effects of pre-exposure and post-exposure vaccines in tuberculosis control

Epidemic control strategies alter the spread of the disease in the host population. In this paper, we describe and discuss mathematical models that can be used to explore the potential of pre-exposure and post-exposure vaccines currently under development in the control of tuberculosis. A model with bacille Calmette-Guerin (BCG) vaccination for the susceptibles and treatment for the infectives is first presented. The epidemic thresholds known as the basic reproduction numbers and equilibria for the models are determined and stabilities are investigated. The reproduction numbers for the models are compared to assess the impact of the vaccines currently under development. The centre manifold theory is used to show the existence of backward bifurcation when the associated reproduction number is less than unity and that the unique endemic equilibrium is locally asymptotically stable when the associated reproduction number is greater than unity. From the study we conclude that the pre-exposure vaccine currently under development coupled with chemoprophylaxis for the latently infected and treatment of infectives is more effective when compared to the post-exposure vaccine currently under development for the latently infected coupled with treatment of the infectives.     

Changing Epidemiological Characteristics of Hepatitis A in Zhejiang Province,China: Increased Susceptibility in Adults

BackgroundHepatitis A is a common acute hepatitis caused by hepatitis A virus (HAV). Annually, it affects 1.4 million people worldwide. Between 1991 and 1994, HAV infections were highly endemic in Zhejiang Province (China), with 78,720 reported HAV infections per year. Hepatitis A vaccine came on the market in 1995 and was implemented for voluntary immunization. Since 2008, hepatitis A vaccine has been integrated into the national childhood routine immunization program.ObjectiveTo understand the current epidemiological profile of hepatitis A in Zhejiang Province since hepatitis A vaccine has been available for nearly two decades.MethodsThis study used the 2005–2014 National Notifiable Diseases Reporting System data to evaluate the incidence rate of notified hepatitis A cases in Zhejiang Province.ResultsThe overall trend of incidence rate of notified hepatitis A cases significantly decreased from 2005 to 2014 (P< 0.001). During the study period, the reported incidence rate in individuals aged ≤19 years declined to the historically lowest record in 2014. Compared with individuals aged ≤19 years, those aged ≥20 years showed the highest incidence rate (P< 0.001). Majority of HAV infected cases were Laborers, accounting for approximately 70% of reported cases.ConclusionsChildhood immunization strategy with hepatitis A vaccine seemed to be effective in decreasing notified hepatitis A incidence rate in individuals aged ≤19 years. Those aged ≥20 years were observed to be the most susceptible population. The vast majority of hepatitis A cases were notified among Laborers. Therefore, we strongly suggest that future preventive and control measures should focus more on adults, particularly Laborers, in addition to the current childhood hepatitis A vaccination programme.     

Proposal for changing the ministerial instructions for antirabies prophylaxis in the light of the experience of the Centro Antirabbico di Roma

Records of clinical assistance and of post-exposure antirabies prophylaxis from 4820 outpatients who attended the Antirabies Center of Rome following animal bites in 1986 were analysed. We observed a high proportion of people submitted to active immunization (44% received at least one shot of HDCV vaccine) in spite of the fact that rabies is absent from Central Italy since many decades in both wild and domestic animals. These considerations suggest the opportunity of a major revision of the official recommendations for rabies prevention, and we feel that different policies should be adopted in rabies enzootic areas (such as Northern Italy) compared to those where the risk is only potential. Immunization should be avoided after bites by rodents; passive immunization should be added to the vaccine after bites by wild animals in enzootic areas, while bites by cats and dogs, even uncaptured, will not be necessarily followed by vaccination in non enzootic areas.     

Antibody Response to a Human Diploid Cell Rabies Vaccine

An experimentally killed rabies virus vaccine prepared in a human diploid cell strain (WI-38)—Wyeth rabies vaccine (WRV)—was used by various injection schedules in two separate studies to define more closely in human volunteer subjects an effective vaccination schedule for pre- or postexposure immunization, particularly for donors of rabies-hyperimmune plasma. To permit valid comparisons between our results and those of other workers, antibody levels achieved were expressed in terms of international units (IU) per milliliter of serum. Antibody response of previously nonvaccinated persons were only modest after a single dose of WRV, never reaching a level higher than 0.80 IU/ml over a 56-day testing period. Moreover, antibody was not detected at 0.16 IU/ml before the 14th day, either after a single dose or after two doses given 3 days apart. The best response followed four doses of WRV given within 4 weeks. This schedule resulted in the highest rate of seroconversion to the ≥6 IU/ml antibody level required of potential rabies-immune plasma donors. Giving the first vaccine dose in aluminum hydroxide diluent did not enhance the antibody response. There was a definite suggestion in the various injection schedules that higher and more sustained antibody levels were reached when the interval between the first and second vaccine doses was longest. The greater immunogenicity of WRV as compared with duck embryo vaccine was best demonstrated by the fact that a single booster dose of duck embryo vaccine to previously vaccinated individuals resulted in only a sevenfold antibody rise during the following 56 days, whereas a booster dose of WRV elicited a 69-fold rise. Al(OH)₃ in the first dose of WRV had no effect, but the enhancing effect of a longer interval between vaccine doses was noted once again; 20 of 20 subjects who received three doses of WRV with 4 weeks between doses developed good levels of rabies antibody, and 19 exceeded 6 IU/ml.     

Propagation of vaccine strain of duck enteritis virus in a cell line of duck origin as an alternative production system to propagation in embryonated egg

Duck virus enteritis (DVE) also known as duck plague, is a viral infection of ducks caused by duck enteritis virus (DEV). The control of the disease is mainly done by vaccination with a chicken embryo-adapted live virus that is known to be poorly immunogenic and affords partial protection. Further, the risk of harboring other infectious agents in the embryo particularly the deadly and zoonotic avian influenza virus is also high. In this paper, we report propagation of a chicken embryo-adapted vaccine strain of duck enteritis virus in duck embryo fibroblast (DEF) cell line. Thirty serial passages were done in DEF cell that made the vaccine virus further attenuated which was tested in ducks. The growth behaviors of the virus in DEF cells were studied and at 30th passage level the virus titre was found to be 10^6.8 TCID₅₀/ml. Ducks were immunized with this virus and challenged after 21 days with high dose of virulent DEV. All the immunized ducks withstood challenge with no clinical symptoms in any of the ducks while all the control ducks died. DEF cell which is free from other infectious agents appears to be a good system for cultivation of duck enteritis virus vaccine strain.     

Multiple alternating immunizations with DNA vaccine and replication incompetent adenovirus expressing gB of pseudorabies virus protect animals against lethal virus challenge

The prime-boost vaccination with DNA vaccine and recombinant viral vector has emerged as an effective prophylactic strategy to control infectious diseases. Here, we compared the protective immunities induced by multiple alternating immunizations with DNA vaccine (pCIgB) and replication-incompetent adenovirus (Ad-gB) expressing glycoprotein gB of pseudorabies virus (PrV). The platform of pCIgB-prime and Ad-gB-boost induced the most effective immune responses and provided protection against virulent PrV infection. However, priming with pCIgB prior to vaccinating animals by the DNA vaccine-prime and Ad-boost protocol provided neither effective immune responses nor protection against PrV. Similarly, boosting with Ad-gB following immunization with DNA vaccine-prime and Ad-boost showed no significant responses. Moreover, whereas the administration of Ad-gB for primary immunization induced Th2-type-biased immunity, priming with pCIgB induced Th1-type-biased immunity, as judged by the production of PrV-specific IgG isotypes and cytokine IFN-gamma. These results indicate that the order and injection frequency of vaccine vehicles used for heterologous prime-boost vaccination affect the magnitude and nature of the immunity. Therefore, our demonstration implies that the prime-boost protocol should be carefully considered and selected to induce the desired immune responses.     

国产甲型肝炎灭活疫苗用于儿童免疫效果研究

为了探讨国产甲型肝炎灭活疫苗在儿童中应用的免疫效果,选择2～15岁抗-HAV阴性健康易感儿童91名作为接种对象,采用0、6程序接种国产甲型肝炎灭活疫苗250U／剂,观察免疫后的局部反应和全身反应,并于全程免疫后一个月检测抗-HAV阳转率和抗体GMT。结果91例观察对象在初免和加强免疫后均未见即时副反应,只在8～72小时内出现轻微的一过性局部和全身反应。全程免疫后一个月抗-HAV阳转率为100％。抗体GMT为14 407mIU／ml。国产甲肝灭活疫苗在儿童中应用具有良好的安全性和免疫原性,采用0、6个月程序可获得高滴度抗体。     

Public health response to an anthrax attack: an evaluation of vaccination policy options

A discrete-time, deterministic, compartmental model was developed and analyzed to provide insight into how the use of anthrax vaccine before or after a large-scale attack can reduce casualties. The model accounts for important response and protection factors such as antibiotic and vaccine efficacy, the protective effects of buildings, the timing of emergency response, and antibiotic adherence and vaccine coverage in the population prior to the attack. The relative benefit of pre- versus post-exposure vaccination is influenced by the timing of the post-exposure antibiotic distribution campaign as well as assumptions of antibiotic adherence. The results indicate that, regardless of which vaccination policy is adopted, a rapid and effective post-attack medical response has a large impact on the number of lives that can be saved by a post-exposure prophylaxis (PEP) campaign. A sensitivity analysis of the model indicates that uncertainty in medical efficacy and the time to initiate a PEP campaign are the model parameters that have the greatest impact on the number of predicted deaths. It is shown that for each day that a mass prophylaxis campaign is delayed, more casualties and deaths result than for each day that the completion of the campaign is delayed.     

Four years of measles elimination in the Czech Socialist Republic

In 1982, Czechoslovakia succeeded in eliminating measles infection throughout the country. The paper describes the strategy of the measles immunization program following its introduction in 1969, showing it to reflect the objective epidemiological situation as revealed by the regular immunological surveys carried out in a broad population sample. As it turned out, decisive for achieving and maintaining a permanent measles elimination in the country was the introduction of second vaccination into the regular immunization schedule. Since 1982, its timing of is from 6 to 10 months after primary immunization. Over the 4-year period between 1982 and 1985, confirmed measles occurred only sporadically in the CSR, 115 cases altogether, and of these as many as 67 were classified as imported or their immediate contacts (38 measles patients were tourists from abroad). Of these 115 measles cases, 52 had had vaccination prior to acquiring the disease, 46 were individuals who had never before been vaccinated and in the remaining 17 patients no vaccination data were available. The vaccine failures, at least in 18 cases, could have been explained by the primary immunization prior to reaching 15 months of age. According to the estimates, at least 670 thousand cases of measles, 470 deaths, 100 thousand complications and some 33 thousand hospitalizations had been averted between 1972 and 1985 on the territory of CSR as a result of the introduction of the measles immunization program in Czechoslovakia.     

Harnessing Case Isolation and Ring Vaccination to Control Ebola

As a devastating Ebola outbreak in West Africa continues, non-pharmaceutical control measures including contact tracing, quarantine, and case isolation are being implemented. In addition, public health agencies are scaling up efforts to test and deploy candidate vaccines. Given the experimental nature and limited initial supplies of vaccines, a mass vaccination campaign might not be feasible. However, ring vaccination of likely case contacts could provide an effective alternative in distributing the vaccine. To evaluate ring vaccination as a strategy for eliminating Ebola, we developed a pair approximation model of Ebola transmission, parameterized by confirmed incidence data from June 2014 to January 2015 in Liberia and Sierra Leone. Our results suggest that if a combined intervention of case isolation and ring vaccination had been initiated in the early fall of 2014, up to an additional 126 cases in Liberia and 560 cases in Sierra Leone could have been averted beyond case isolation alone. The marginal benefit of ring vaccination is predicted to be greatest in settings where there are more contacts per individual, greater clustering among individuals, when contact tracing has low efficacy or vaccination confers post-exposure protection. In such settings, ring vaccination can avert up to an additional 8% of Ebola cases. Accordingly, ring vaccination is predicted to offer a moderately beneficial supplement to ongoing non-pharmaceutical Ebola control efforts.     

血源乙肝疫苗人体反应及免疫效果观察报告

对我所１９８５年以来生产的１６０批血源乙型肝炎疫苗进行了３６８０例的现场人体观察,结果表明该疫苗接种后,全身及局部反应轻微,在随访期间未显示任何乙型肝炎病毒感染证据;儿童３针免疫后３个月抗－ＨＢｓ平均血清阳转率即达到９８％以上,具有高度的免疫原性。     

AdHu5Ag85A Respiratory Mucosal Boost Immunization Enhances Protection against Pulmonary Tuberculosis in BCG-Primed Non-Human Primates

Persisting high global tuberculosis (TB) morbidity and mortality and poor efficacy of BCG vaccine emphasizes an urgent need for developing effective novel boost vaccination strategies following parenteral BCG priming in humans. Most of the current lead TB vaccine candidates in the global pipeline were developed for parenteral route of immunization. Compelling evidence indicates respiratory mucosal delivery of vaccine to be the most effective way to induce robust local mucosal protective immunity against pulmonary TB. However, despite ample supporting evidence from various animal models, there has been a lack of evidence supporting the safety and protective efficacy of respiratory mucosal TB vaccination in non-human primates (NHP) and humans. By using a rhesus macaque TB model we have evaluated the safety and protective efficacy of a recombinant human serotype 5 adenovirus-based TB vaccine (AdHu5Ag85A) delivered via the respiratory mucosal route. We show that mucosal AdHu5Ag85A boost immunization was safe and well tolerated in parenteral BCG-primed rhesus macaques. A single AdHu5Ag85A mucosal boost immunization in BCG-primed rhesus macaques enhanced the antigen–specific T cell responses. Boost immunization significantly improved the survival and bacterial control following M.tb challenge. Furthermore, TB-related lung pathology and clinical outcomes were lessened in BCG-primed, mucosally boosted animals compared to control animals. Thus, for the first time we show that a single respiratory mucosal boost immunization with a novel TB vaccine enhances protection against pulmonary TB in parenteral BCG-primed NHP. Our study provides the evidence for the protective potential of AdHu5Ag85A as a respiratory mucosal boost TB vaccine for human application.     

Reactogenicity and antigenic activity of a chromatographic cultured purified and concentrated inactivated dried vaccine against tick-borne encephalitis

The study of the characteristics of a new dried tissue-culture purified concentrated inactivated vaccine against tick-borne encephalitis, manufactured in the USSR, has revealed that the preparation is moderately reactogenic and produces no definite side effects in the vaccinees. In the process of the controlled epidemiological trial the optimum vaccination schedule for the primary immunization of adults against tick-borne encephalitis with the new preparation has been determined by the study of serum samples from the vaccinees in the hemagglutination inhibition test and the neutralization test in tissue culture. In accordance with this vaccination schedule the course of primary immunization with the chromatographic variant of the concentrated vaccine consists of two injections in a dose of 0.5 ml, made at an interval of 6 months.     

Management of 41 persons exposed to a rabid dog: unplanned experience with human diploid vaccine.

Thirty-six persons -- veterinarians, technicians and students at a veterinary clinic -- were unwittingly exposed to a rabid dog over a period of 21/2 days. One veterinarian received a penetrating bite, two other individuals were grabbed by the dog but the skin was not penetrated, and many were exposed to saliva or urine or both. In addition, the owner of the dog and his wife and three children, while not bitten, were exposed to saliva. The diagnosis was made post mortem when specimens of the dog''s brain were examined by indirect fluorescent antibody testing. All but one of the students had been vaccinated against rabies with hamster kidney vaccine, but eight members of the veterinary college''s staff had not been so vaccinated. Treatment started with duck embryo vaccine; if necessary, rabies (human) immune globulin was also given. When one student reacted severely to the first dose of duck embryo vaccine permission was sought to bring a human diploid vaccine into Canada. In five patients the human diploid vaccine was substituted for the duck embryo vaccine because of severe reactions to the latter. Twenty-five staff members and the family of five received both vaccines. Reactions to the human diploid vaccine were minor and transient. Recommendations include the early licensing of the human diploid vaccine in Canada.     

Intranasal immunization with recombinant vesicular stomatitis virus expressing murine cytomegalovirus glycoprotein B induces humoral and cellular immunity

Cytomegalovirus is a leading cause of morbidity and mortality among neonatal and immunocompromised patients. The use of vaccine prophylaxis continues to be an effective approach to reducing viral infections and their associated diseases. Murine cytomegalovirus (mCMV) has proven to be a valuable animal model in determining the efficacy of newly developed vaccine strategies in vivo. Live recombinant vesicular stomatitis viruses (rVSV) have successfully been used as vaccine vectors for several viruses to induce strong humoral and cellular immunity. We tested the ability of intranasal immunization with an rVSV expressing the major envelope protein of mCMV, glycoprotein B (gB), to protect against challenge with mCMV in a mouse model. rVSV-gB-infected cells showed strong cytoplasmic and cell surface expression of gB, and neutralizing antibodies to gB were present in mice after a single intranasal vaccination of VSV-gB. After challenge with mCMV, recovery of live virus and viral DNA was significantly reduced in immunized mice. In addition, primed splenocytes produced a CD8+ IFNgamma response to gB. The ability to induce an immune response to a gene product through mucosal vaccination with rVSV-gB represents a potentially effective approach to limiting CMV-induced disease.     

New vaccines for immunization of man: new approaches towards the prevention of rabies in man

Cell culture rabies vaccines for human use, highly immunogenic and well tolerated, are now used for pre-exposure immunization as well as for post-exposure treatment. Presently available cell culture rabies vaccines induce immunity against the SAD modified live rabies virus used for oral immunization of foxes. They also induce immunity against the newly identified European bat rabies virus (Duvenhage).     

Use of a Recombinant Vaccinia Virus Expressing Interferon Gamma for Post-Exposure Protection against Vaccinia and Ectromelia Viruses

Post-exposure vaccination with vaccinia virus (VACV) has been suggested to be effective in minimizing death if administered within four days of smallpox exposure. While there is anecdotal evidence for efficacy of post-exposure vaccination this has not been definitively studied in humans. In this study, we analyzed post-exposure prophylaxis using several attenuated recombinant VACV in a mouse model. A recombinant VACV expressing murine interferon gamma (IFN-γ) was most effective for post-exposure protection of mice infected with VACV and ectromelia virus (ECTV). Untreated animals infected with VACV exhibited severe weight loss and morbidity leading to 100% mortality by 8 to 10 days post-infection. Animals treated one day post-infection had milder symptoms, decreased weight loss and morbidity, and 100% survival. Treatment on days 2 or 3 post-infection resulted in 40% and 20% survival, respectively. Similar results were seen in ECTV-infected mice. Despite the differences in survival rates in the VACV model, the viral load was similar in both treated and untreated mice while treated mice displayed a high level of IFN-γ in the serum. These results suggest that protection provided by IFN-γ expressed by VACV may be mediated by its immunoregulatory activities rather than its antiviral effects. These results highlight the importance of IFN-γ as a modulator of the immune response for post-exposure prophylaxis and could be used potentially as another post-exposure prophylaxis tool to prevent morbidity following infection with smallpox and other orthopoxviruses.     

A Novel Replication-Competent Vaccinia Vector MVTT Is Superior to MVA for Inducing High Levels of Neutralizing Antibody via Mucosal Vaccination

Mucosal vaccination offers great advantage for inducing protective immune response to prevent viral transmission and dissemination. Here, we report our findings of a head-to-head comparison of two viral vectors modified vaccinia Ankara (MVA) and a novel replication-competent modified vaccinia Tian Tan (MVTT) for inducing neutralizing antibodies (Nabs) via intramuscular and mucosal vaccinations in mice. MVTT is an attenuated variant of the wild-type VTT, which was historically used as a smallpox vaccine for millions of Chinese people. The spike glycoprotein (S) of SARS-CoV was used as the test antigen after the S gene was constructed in the identical genomic location of two vectors to generate vaccine candidates MVTT-S and MVA-S. Using identical doses, MVTT-S induced lower levels (∼2-3-fold) of anti- SARS-CoV neutralizing antibodies (Nabs) than MVA-S through intramuscular inoculation. MVTT-S, however, was capable of inducing consistently 20-to-100-fold higher levels of Nabs than MVA-S when inoculated via either intranasal or intraoral routes. These levels of MVTT-S-induced Nab responses were substantially (∼10-fold) higher than that induced via the intramuscular route in the same experiments. Moreover, pre-exposure to the wild-type VTT via intranasal or intraoral route impaired the Nab response via the same routes of MVTT-S vaccination probably due to the pre-existing anti-VTT Nab response. The efficacy of intranasal or intraoral vaccination, however, was still 20-to-50-fold better than intramuscular inoculation despite the subcutaneous pre-exposure to wild-type VTT. Our data have implications for people who maintain low levels of anti-VTT Nabs after historical smallpox vaccination. MVTT is therefore an attractive live viral vector for mucosal vaccination.     

Recent Advances in Toxoplasma gondii Immunotherapeutics

Toxoplasmosis is an opportunistic infection caused by the protozoan parasite Toxoplasma gondii. T. gondii is widespread globally and causes severe diseases in individuals with impaired immune defences as well as congenitally infected infants. The high prevalence rate in some parts of the world such as South America and Africa, coupled with the current drug treatments that trigger hypersensitivity reactions, makes the development of immunotherapeutics intervention a highly important research priority. Immunotherapeutics strategies could either be a vaccine which would confer a pre-emptive immunity to infection, or passive immunization in cases of disease recrudescence or recurrent clinical diseases. As the severity of clinical manifestations is often greater in developing nations, the development of well-tolerated and safe immunotherapeutics becomes not only a scientific pursuit, but a humanitarian enterprise. In the last few years, much progress has been made in vaccine research with new antigens, novel adjuvants, and innovative vaccine delivery such as nanoparticles and antigen encapsulations. A literature search over the past 5 years showed that most experimental studies were focused on DNA vaccination at 52%, followed by protein vaccination which formed 36% of the studies, live attenuated vaccinations at 9%, and heterologous vaccination at 3%; while there were few on passive immunization. Recent progress in studies on vaccination, passive immunization, as well as insights gained from these immunotherapeutics is highlighted in this review.     

Effective post-exposure treatment of Ebola infection

Ebola viruses are highly lethal human pathogens that have received considerable attention in recent years due to an increasing re-emergence in Central Africa and a potential for use as a biological weapon. There is no vaccine or treatment licensed for human use. In the past, however, important advances have been made in developing preventive vaccines that are protective in animal models. In this regard, we showed that a single injection of a live-attenuated recombinant vesicular stomatitis virus vector expressing the Ebola virus glycoprotein completely protected rodents and nonhuman primates from lethal Ebola challenge. In contrast, progress in developing therapeutic interventions against Ebola virus infections has been much slower and there is clearly an urgent need to develop effective post-exposure strategies to respond to future outbreaks and acts of bioterrorism, as well as to treat laboratory exposures. Here we tested the efficacy of the vesicular stomatitis virus-based Ebola vaccine vector in post-exposure treatment in three relevant animal models. In the guinea pig and mouse models it was possible to protect 50% and 100% of the animals, respectively, following treatment as late as 24 h after lethal challenge. More important, four out of eight rhesus macaques were protected if treated 20 to 30 min following an otherwise uniformly lethal infection. Currently, this approach provides the most effective post-exposure treatment strategy for Ebola infections and is particularly suited for use in accidentally exposed individuals and in the control of secondary transmission during naturally occurring outbreaks or deliberate release.