Rabies post-exposure vaccination in 2 visits within a week: A 4-site intradermal regimen

Rabies is fatal in all unvaccinated patients bitten by dogs, and so post-exposure vaccine regimens must be robust enough to ensure their survival under all conditions. Treatment tends to be excessive for most people, but there is justified anxiety about reducing vaccine dosage and shortening regimens. Recently, World Health Organisation (WHO) recommended one week primary post-exposure intradermal regimens requiring 3 clinic visits, but these are unlikely to prove economical where rabies vaccination is most needed, in deprived rural areas of Africa and Asia.A highly immunogenic regimen involving two doses of intradermal vaccine given one week apart has advantages over other regimens. Anyone exposed to a possibly rabid animal would be given intradermal (ID) injections at 4 sites using a whole vial of vaccine. Those who had not been previously vaccinated would be given 2-site ID injections using half a vial one week later. Those who might be immunosuppressed could be given an optional single ID dose on day 28. The rationale for this regimen is discussed in the context of the recently revised WHO recommendations for rabies prophylaxis.     

Rabies immunosome (subunit vaccine) structure and immunogenicity. Pre- and post-exposure protection studies

Rabies immunosomes (glycoprotein anchored on pre-formed liposomes) have been prepared in order to study their structural, biological and immunological properties. The glycoprotein molecules appear to have the same orientation on the immunosome as on the viral particle: (1) electron microscopy analysis shows particles of 40 to 70 nm with spikes protruding outward, (2) one particular epitope shows the same accessibility to a neutralizing monoclonal antibody as on the viral particle. When injected into animals, rabies immunosomes are cleared from the organism by a process different from that for the liposomes used to anchor the glycoprotein: a higher rate of transition through the spleen is observed with immunosomes than with purified glycoprotein or liposomes. Immunosomes induce high levels of neutralizing antibodies and protect animals against challenge with virulent strains. This protective activity is not altered after several months of storage at 4 degrees C. Furthermore, rabies immunosomes were shown to be efficient in post-exposure treatment of laboratory animals that had been experimentally infected with a lethal dose of a rabies wild strain.     

Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis

The standard six-dose intramuscular (i.m.) rabies post-exposure vaccine regimen using a new purified chick embryo cell (PCEC) vaccine was compared with two economical multisite intradermal (i.d.) PCEC regimens, a multisite i.m. PCEC schedule and a subcutaneous regimen using a suckling mouse brain (SMB) rabies vaccine manufactured in Thailand. The neutralizing antibody results for the four-site and eight-site i.d. and the standard i.m. PCEC regimens were similar over 3 months. A three-site i.m. PCEC regimen had no advantage. The SMB vaccine gave the lowest antibody levels. Human rabies immune globulin therapy significantly increased the GMT of all groups on day 7, unlike equine antirabies serum (EARS). Both antisera suppressed antibody responses to PCEC on days 14 and 28. Three generalized reactions probably related to EARS were the only serious side effects. An eight-site i.d. PCEC vaccine regimen proved as immunogenic as the routine i.m. schedule and, if implemented as post-exposure prophylaxis, would be the cheapest widely available tissue culture vaccine regimen. The protective efficiency should now be tested in patients bitten by rabid animals.     

Rabies DNA vaccination of non-human primates: post-exposure studies using gene gun methodology that accelerates induction of neutralizing antibody and enhances neutralizing antibody titers

Pre-exposure DNA vaccination protects non-human primates against rabies virus. Post-exposure protection of monkeys against rabies virus by DNA vaccination has not been attempted. Presumably, post-exposure experiments have not been undertaken because neutralizing antibody is usually slow to be induced after DNA vaccination. In this study, we initially attempted to accelerate the induction of neutralizing antibody by varying the route and site of DNA vaccination and booster frequency. Gene gun (GG) vaccinations above axillary and inguinal lymph nodes or in ear pinnae generated higher levels of neutralizing antibody than intradermal (ID) needle vaccinations in the pinnae. Concurrent GG booster vaccinations above axillary and inguinal lymph nodes and in ear pinnae, 3 days after primary vaccination, accelerated detectable neutralizing antibody. GG booster vaccinations also resulted in higher neutralizing antibody levels and increased the durability of this response. Post-exposure vaccination with DNA or the human diploid cell vaccine (HDCV), in combination with an one-time treatment with human rabies immune globulin (HRIG), protected 50 and 75% of the monkeys, respectively, as compared to 75% mortality of the controls. These data will be useful for the refinement, development, and implementation of future pre- and post-exposure rabies DNA vaccination studies.     

A pilot study on intradermal vaccination of Japanese rabies vaccine for pre-exposure immunization

Japanese rabies vaccine, a purified chick embryo cell vaccine manufactured by Kaketsuken (PCEC-K), is normally given subcutaneously; however, this requires a large amount of vaccine, and the pre-exposure vaccination regimen requires 6 months to complete. These factors often hamper appropriate vaccination. Therefore, we examined whether this vaccine could induce adequate level of viral neutralizing antibody (VNA) when vaccinated according to the World Health Organization (WHO) intradermal regimen. Our pilot study showed that this regimen resulted in all subjects developing adequate VNA levels. Intradermal route was effective not only for pre-exposure but also for booster vaccination. The intradermal PCEC-K regimen was found to be safe and effective in inducing adequate VNA levels with the use of a smaller quantity of vaccine and within a shorter period of time.     

Safety and efficacy of transcutaneous vaccination using a patch with the live-attenuated measles vaccine in humans

Transcutaneous immunisation (TCI) using a skin patch is a non-invasive vaccination route relevant to mass vaccination against infectious diseases. This phase I/II clinical study, documents that TCI of human adult volunteers with the live-attenuated measles vaccine ROUVAX((R)) is safe and poorly reactogenic. It promotes induction of measles-specific salivary IgA and a tendency to increased frequency of MV-specific IFNgamma-producing T cells. However, in contrast to the subcutaneous route, TCI failed to evoke neutralising MV-specific serum antibodies. Thus, alternative delivery methods and/or devices providing optimal uptake by skin DC should be considered for live-attenuated virus vaccines, such as the measles vaccine.     

Rabies post-exposure prophylaxis vaccination with purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccine (PVRV) in a four-site intradermal schedule (4-0-2-0-1-1): an immunogenic, cost-effective and practical regimen

Currently, two intradermal (ID) regimens for rabies post-exposure prophylaxis (PEP) are recommended by WHO and used in countries where approved by national authorities: the Thai Red Cross (TRC) two-site ID regimen and the eight-site ID regimen. Besides these WHO recommended schedules, a new economical four-site ID regimen was evaluated that reduces the cost of PEP by up to 80%, when compared with the standard intramuscular Essen regimen, reduces the number of visits required for the patients when compared with the TRC regimen, and is more convenient than the eight-site regimen. To determine the immunogenicity of the ID four-site PEP regimen (4-0-2-0-1-1), 180 healthy volunteers were randomized to receive 0.1 mL volumes of PCECV or PVRV administered ID over both left and right shoulders and both deltoid regions on day 0, both deltoid regions on day 7 and over one deltoid region on days 30 and 90. Regardless of the vaccine, every subject developed rabies virus neutralizing antibody (RVNA) titers above 0.5 IU/mL by day 14, as determined by rapid fluorescent focus inhibition test (RFFIT) using a homologous test system. Two weeks after the last dose of vaccine, RVNA titers were all above 0.5 IU/mL (day 104). Geometric mean titers were similar throughout the study period. Both vaccines were well tolerated. These results demonstrate that a new four-site ID PEP regimen is a cost-effective and convenient alternative to IM (Essen or Zagreb) or ID (TRC or eight-site) regimens, especially using a 1 mL vial of vaccine (PCECV).     

Cost-effectiveness of an influenza vaccination program offering intramuscular and intradermal vaccines versus intramuscular vaccine alone for elderly

BackgroundIntradermal (ID) injection is an alternative route for influenza vaccine administration in elderly with potential improvement of vaccine coverage. This study aimed to investigate the cost-effectiveness of an influenza vaccination program offering ID vaccine to elderly who had declined intramuscular (IM) vaccine from the perspective of Hong Kong public healthcare provider.MethodsA decision analytic model was used to simulate outcomes of two programs: IM vaccine alone (IM program), and IM or ID vaccine (IM/ID program) in a hypothetic cohort of elderly aged 65 years. Outcome measures included influenza-related direct medical cost, infection rate, mortality rate, quality-adjusted life years (QALYs) loss, and incremental cost per QALY saved (ICER). Model inputs were derived from literature. Sensitivity analyses evaluated the impact of uncertainty of model variables.ResultsIn base-case analysis, the IM/ID program was more costly (USD52.82 versus USD47.59 per individual to whom vaccine was offered) with lower influenza infection rate (8.71% versus 9.65%), mortality rate (0.021% versus 0.024%) and QALYs loss (0.00336 versus 0.00372) than the IM program. ICER of IM/ID program was USD14,528 per QALY saved. One-way sensitivity analysis found ICER of IM/ID program to exceed willingness-to-pay threshold (USD39,933) when probability of influenza infection in unvaccinated elderly decreased from 10.6% to 5.4%. In 10,000 Monte Carlo simulations of elderly populations of Hong Kong, the IM/ID program was the preferred option in 94.7% of time.ConclusionsAn influenza vaccination program offering ID vaccine to elderly who had declined IM vaccine appears to be a highly cost-effective option.     

Rabies cell culture vaccines reconstituted and stored at 4 degrees C for 1 year prior to use protect mice against rabies virus

Human exposure to rabid dogs in developing countries is an ongoing problem that continues to demand effective, safe, and affordable post-exposure rabies vaccinations. Sheep and suckling mouse brain rabies vaccines used in developing countries are being replaced by expensive inactivated-virus cell culture vaccines. Human studies using cell culture vaccines have determined that cost is reduced and protection is maintained by injecting the unused portion of vaccines that have been reconstituted and stored refrigerated for 1 week. Here we determined whether reconstituted purified chick embryo cell and human diploid cell vaccine that had been stored at 4 degrees C for intervals up to 1 year elicit neutralizing antibody, and protect mice against rabies virus. Undiluted, or 1:5 and 1:25 dilutions of both vaccines injected immediately after reconstitution, or after reconstitution and storage at 4 degrees C for 1 week, 1 month, 3 months, 6 months or 1 year elicited high levels of neutralizing antibody and protected 100% of the mice injected with rabies virus.     

暴露后843例狂犬病疫苗接种者流行病学分析

目的分析上高县动物致伤及暴露处置状况,为进一步做好狂犬病暴露后预防处置提供依据。方法收集2007年上高县疾病预防控制中心狂犬病预防接种门诊资料,对狂犬病疫苗接种者及其处置情况作统计分析。结果 843例暴露后免疫接种者中男女之比为1.57:1,致伤的高危年龄段为15岁及30～44岁,以学生和农民居多,7、8月份为致伤高峰。伤人动物以犬最多,其次为猫。致伤部位以下肢和上肢为主,Ⅲ度和Ⅱ度暴露者占96.69%。24h内及时就诊处置占91.10%。70.34%的暴露者进行了规范的清创消毒,完成狂犬病疫苗全程接种的占99.05%,7.59%的暴露者使用了人源狂犬病免疫球蛋白。结论暴露后预防处置对预防狂犬病发挥了重要作用,今后仍需落实暴露人群的规范处置,加强狂犬病防治知识宣传,提高高危人群的自我保护意识。     

Improved antibody responses in infants less than 1 year old using intradermal influenza vaccination

BACKGROUND: Antibody response to influenza vaccine is limited in early. Infants have poorer hemagglutination-inhibiting antibody responses than 12-month-old. Intradermal administration reportedly elicited immune responses similar to or better than a standard intramuscular dose. We hypothesized that intradermal injection could achieve a better response in infants than subcutaneous injection. METHODS: We randomized 34 healthy infants 6-12 months old to either intradermal immunization (0.1 ml of trivalent influenza vaccine containing at least 3 microg of hemagglutinin antigen per strain) or subcutaneous immunization (also 0.1 ml). Changes in hemagglutination inhibition titer were compared using Mann-Whitney U-test, changes in positivity rate, seroconversion, and seroprotection. Local and systemic adverse events were assessed. RESULTS: All 32 infants received both injections. Antibody titers on days at 42 after intradermal injection were significantly greater than subcutaneous injection (P=0.032 in A/New Caledonia (H1N1), 0.019 in A New York (H3N2) and 0.044 in B/Shanghai. Positive titers for A New York (H3N2) were attained significantly more often after intradermal (73.3%) than subcutaneous injection (23.5%) on day 28, and significantly more often 42 days after intradermal injection (93.3% for A/New Caledonia (H1N1) and 73.3% for B/Shanghai) than after subcutaneous injection. Positive rates for other stains were similar between groups on days 28 and 42. Seroconversion rates were similar between groups. Seroprotection on day 42 for A New York (H3N2) was significantly greater in the intradermal (86.7%) than in the subcutaneous group (35.3%). Seroprotection rates for other stains were similar. CONCLUSIONS: Intradermal administration to infants of two doses of influenza vaccine was more immunogenic than subcutaneous injection. Seroconversion and seroprotection rates remained insufficient. Further study of route, quantity, and frequency are needed to improve of responses in infants.     

Antibody response of patients after postexposure rabies vaccination with small intradermal doses of purified chick embryo cell vaccine or purified Vero cell rabies vaccine

Although the introduction of tissue culture vaccines for rabies has dramatically improved the immunogenicity and safety of rabies vaccines, they are often prohibitively expensive for developing countries. To examine whether smaller doses of these vaccines could be used, we tested the safety and immunogenicity of purified chick embryo cell vaccine (PCECV) on 211 patients in Thailand with World Health Organization (WHO) category II and III exposures to rabies. The patients presented at two Thai hospitals and were randomized into three groups. Patients in Group 1 received 0.1 ml PCECV intradermally at two sites on days 0, 3, 7, and at one site on days 30 and 90. Group 2 was treated similarly, except that purified Vero cell rabies vaccine (PVRV) was used instead of PCECV. Group 3 received 1.0 ml PCECV intramuscularly on days 0, 3, 7, 14, 30 and 90. After 0, 3, 7, 14, 30 and 90 days serum was collected from the subjects and the geometric mean titres (GMTs) of rabies virus neutralizing antibody determined. After 14 days the GMT of 59 patients vaccinated intradermally with PCECV was equivalent to that of patients who received PVRV. Adverse reactions were more frequent in patients who received vaccines intradermally, indicating the reactions were associated with the route of injection, rather than the vaccine per se. We conclude that PCECV is a safe and highly immunogenic vaccine for postexposure rabies vaccination when administered intradermally in 0.1-ml doses using the two-site method ("2,2,2,0,1,1") recommended by WHO.     

Immunogenicity and safety of intradermal influenza vaccine in children

In order to compare the immunogenicity and safety of different doses of trivalent influenza vaccine (TIV) administered intradermallly (ID) with those evoked by a full dose of intramuscular (IM) virosomal-adjuvanted influenza vaccine (VA-TIV), 112 previously primed healthy children aged ≥3 years were randomised to receive 9 μg or 15 μg of each strain of ID-TIV, or a full IM dose (15 μg of each strain) of VA-TIV. The A/H1N1 and A/H3N2 seroconversion and seroprotection rates were ≥90% and geometric mean titres (GMTs) increased 3.2-14.9 times without any statistically significant between-group differences; however, the seroconversion and seroprotection rates against the B strain were significantly higher in the children receiving either ID-TIV dose (p < 0.05) without any differences between them. GMT against B virus was significantly higher in the children receiving the highest dose (p < 0.05). Local reactions were significantly more common among the children receiving either ID-TIV dose (p < 0.05), but systemic reactions were relatively uncommon in all three groups. Our findings suggest that ID-TIV with 15 μg of each viral antigen can confer a significant better protection against influenza than that obtained with the same dose of IM TIV in already primed children aged ≥3 years with an acceptable safety profile. The lower dose of ID-TIV needs further evaluation to analyze persistence of protection.     

Enhanced immunogenicity and protective efficacy of a tetravalent dengue DNA vaccine using electroporation and intradermal delivery

Phase 1 clinical trials with a DNA vaccine for dengue demonstrated that the vaccine is safe and well tolerated, however it produced less than optimal humoral immune responses. To determine if the immunogenicity of the tetravalent dengue DNA vaccine could be enhanced, we explored alternate, yet to be tested, methods of vaccine administration in non-human primates. Animals were vaccinated on days 0, 28 and 91 with either a low (1 mg) or high (5 mg) dose of vaccine by the intradermal or intramuscular route, using either needle-free injection or electroporation devices. Neutralizing antibody, IFN-γ T cell and memory B cell responses were compared to a high dose group vaccinated with a needle-free intramuscular injection delivery device similar to what had been used in previous preclinical and clinical studies. All previously untested vaccination methodologies elicited improved immune responses compared to the high dose needle-free intramuscular injection delivery group. The highest neutralizing antibody responses were observed in the group that was vaccinated with the high dose formulation via intradermal electroporation. The highest IFN-γ T cell responses were also observed in the high dose intradermal electroporation group and the CD8⁺ T cells were the dominant contributors for the IFNγ response. Memory B cells were detected for all four serotypes. More than a year after vaccination, groups were challenged with dengue-1 virus. Both the low and high dose intradermal electroporation groups had significantly fewer days of dengue-1 virus RNAemia compared to the control group. The results from this study demonstrate that using either an electroporation device and/or the intradermal route of delivery increases the immune response generated by this vaccine in non-human primates and should be explored in humans.     

The safety of post-exposure vaccination of mice infected with Mycobacterium tuberculosis

New post-exposure tuberculosis vaccination strategies are being developed to prevent disease in individuals latently infected with Mycobacterium tuberculosis. However, concerns about the potential induction of deleterious Koch-like reactions after immunization of persons with latent tuberculosis has limited progress in assessing the effectiveness of post-exposure vaccination. To evaluate the safety of immunization after M. tuberculosis infection, two mouse models were established, a drug treatment low bacterial burden model and an active disease model. Twelve different M. tuberculosis antigen preparations and vaccines (including DNA, subunit, viral vectored, and live, attenuated vaccines) were evaluated using these mouse models. In the low bacterial burden model, post-exposure vaccination did not induce significant reactivational disease and only injection of BCG evoked increases in lung inflammatory responses at 1 month after the immunizations. Additionally, although significant increases in lung inflammation were seen for animals injected with the hps65 DNA vaccine or a M. tuberculosis culture supernatant preparation, no differences in the survival periods were detected between vaccinated and non-vaccinated mice at 10 months post-immunization using the low bacterial burden model. For the active disease model, significantly more lung inflammation was observed at 1 month after administration of the hsp65 DNA vaccine but none of the antigen preparations tested increased the lung bacterial burdens at this early time point. Furthermore, vaccination of diseased mice with BCG or TB DNA vaccines did not significantly affect mortality rates compared to non-vaccinated controls at 10 months post-immunization. Overall, these data suggest that while the potential risk of inducing Koch-like reactions is low after immunization of persons with latent tuberculosis, extreme caution is still needed as post-exposure vaccines progress from pre-clinical experiments into the initial phases of clinical testing.     

SUPPURATIVE lymphadenitis following intradermal BCG vaccination of preschool children

Regional lymph-node abscesses often occur among infants and young children following BCG vaccination, and the purpose of this study was to find ways to avoid glandular complications, or at least minimize their frequency, without jeopardizing the success of vaccination.Over 1,700 children ranging in age from 6 months to 7 years were vaccinated by one of nine different procedures obtained by various combinations of two strengths of vaccine, two depths of injection, and three volumes of vaccine, in an attempt to reproduce, experimentally, some of the kinds of variation that may occur in practical programmes. Follow-up examinations were made at 10 weeks and at one year, the local and glandular responses being observed and measured and the degree of tuberculin sensitivity assessed by an intradermal 10 TU test.BOTH THE DOSE OF VACCINE AND THE AGE OF THE CHILD WERE FOUND TO HAVE A STRIKING EFFECT ON THE FREQUENCY AND SEVERITY OF LYMPHADENITIS: the larger the dose and the younger the child, the higher the frequency of enlarged or perforated axillary lymph nodes. Furthermore, there was a close association between the findings at the two follow-up periods: with only one exception, children with negligible enlargement of the nodes at the 10-week examination had negligible findings at one year, whereas all the children with enlarged and adherent nodes at 10 weeks had evidence of perforation at one year.THE SIZE OF THE VACCINAL LESION WAS ALSO AFFECTED BY VACCINE DOSE AND BY AGE OF CHILD: the lesion was larger in the younger children and with the stronger doses. The degree of tuberculin sensitivity was affected only slightly by the variations in dose and still less by the age of the child.The size of the wheal raised by intradermal injection of vaccine was found to vary with the age of the child and with the depth of injection as much as it varied with the volume of vaccine injected. There can be no doubt that gauging the dose by the size of the wheal, rather than by the calibrations on a non-leaking syringe, is a very inaccurate procedure. When the dose of vaccine can be accurately measured, a stronger vaccine can be given (and perhaps a stronger degree of immunity attained) without causing an intolerable frequency of suppurative lymphadenitis.     

5200例狂犬疫苗接种者免疫效果观察

目的了解国产纯化狂犬疫苗接种后的效果。方法以5 200例接种狂犬疫苗的暴露者为研究对象,每位对象取静脉血3 ml,分离血清,用酶联免疫吸附测定法（简称ELISA法）检测抗-RA。结果国产纯化狂犬疫苗全程免疫后总抗-RA阳转率为98.27%,性别间分布无差异,而年龄组间存在差异,70岁以上年龄组抗体阳性率较其他组低。使用狂犬病免疫球蛋白和狂犬疫苗联合接种者抗体阳性率为100%,未注射狂犬病免疫球蛋白组抗体阳性率为97.35%。多剂量（针次）接种组与常规接种组抗体阳性率差异有统计学意义（χ^2=26.997,P〈0.05）。结论按免疫程序及时全程注射人用纯化狂犬疫苗,可产生较为理想的保护性抗体,对疑似狂犬、流浪犬和三度咬伤者采用狂犬病免疫球蛋白和狂犬疫苗联合、早期、足量、全程、规则的免疫原则,中老年伤者增大剂量或增加接种针次,均可达到理想的预防效果。     

Studies on correlation between viability of BCG vaccine and tuberculin allergy induced by vaccination in humans

The authors describe two experiments which were carried out to determine whether, and to what extent, there is a correlation between the viability of BCG vaccine and the size of the post-vaccination tuberculin reaction is humans.