Efficacy and safety of measles,mumps, rubella and varicella live viral vaccines in transplant recipients receiving immunosuppressive drugs

Background  This review was designed to summarize published data on the efficacy and safety of live viral vaccines for measles, mumps, rubella, or varicella in post-transplant patients currently on immunosuppression. Data sources  Medline, EMBASE and Evidence Based Medicine Reviews were searched from 1966 to November 2007 for case reports or studies describing the efficacy and/or safety of live attenuated measles, mumps, rubella, or varicella vaccine in children on immunosuppression following solid organ, bone marrow or stem cell transplantation. Results  The review identified 6 case series and 2 case reports describing 114 solid organ transplant recipients and one case series describing 27 bone marrow transplant recipients who had received a combined total of 206 doses of live varicella, measles, mumps, or rubella vaccine while on immunosuppression. Post-immunization titers were in the immune range in 109 of the 171 situations where they were measured following a single dose of vaccine (64%) and in 15 of 22 situations following 2 doses (68%). There were no major safety concerns in this small sample. Conclusion  There are insufficient published data to derive evidence-based guidelines for use of live viral vaccines in transplant recipients on immunosuppression but preliminary data on efficacy and safety suggest that the use of these live viral vaccines in transplant recipients still on immunosuppression could be a reasonable strategy.     

Live vaccines after pediatric solid organ transplant: Proceedings of a consensus meeting, 2018

Growing evidence suggests receipt of live‐attenuated viral vaccines after solid organ transplant (SOT) has occurred and is safe and needed due to lapses in herd immunity. A 2‐day consortium of experts in infectious diseases, transplantation, vaccinology, and immunology was held with the objective to review evidence and create expert recommendations for clinicians when considering live viral vaccines post‐SOT. For consideration of VV and MMR post‐transplant, evidence exists only for kidney and liver transplant recipients. For MMR vaccine post‐SOT, consider vaccination during outbreak or travel to endemic risk areas. Patients who have received antiproliferative agents (eg. mycophenolate mofetil), T cell–depleting agents, or rituximab; or have persistently elevated EBV viral loads, or are in a state of functional tolerance, should be vaccinated with caution and have a more in‐depth evaluation to define benefit of vaccination and net state of immune suppression prior to considering vaccination. MMR and/or VV (not combined MMRV) is considered to be safe in patients who are clinically well, are greater than 1 year after liver or kidney transplant and 2 months after acute rejection episode, can be closely monitored, and meet specific criteria of “low‐level” immune suppression as defined in the document.     

Application of a live varicella vaccine in children with acute leukemia or other malignant diseases.

A live varicella vaccine was used in 11 susceptible children in remission from acute leukemia, ten of whom had been in remission for six months or less, and in 6 children with neuroblastoma and retinoblastoma. In the immunological checkup before vaccination, most of them showed a positive reaction in the skin tests with dinitrochlorobenzene, phytohemagglutinin, purified protein derivative, and viral antigens. Leukopenia (three cases, less than 3,000/cu mm) and decreased IgG level (two cases, 380 mg/dl and 445 mg/dl) were observed in the children with leukemia. Anticancer medication was suspended from one week before vaccination to one week after vaccination. The only clinical reaction was a minute rash that appeared three weeks after vaccination in two children with leukemia and that disappeared within three days. Serological responses by complement fixing and neutralizing (NT) tests were detected in all the vaccinated children four weeks after vaccination, and NT antibody was still detected 28 months after vaccination in the two patients tested. Three of the vaccines were exposed to natural varicella at home and in the classroom 2 to 18 months after vaccination, but they were free from any varicella symptoms.     

Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome)

The package inserts of live viral vaccines include immunodeficiency as a contraindication. Nevertheless, patients with mild forms of immunodeficiency may benefit from vaccination. No published guidelines exist for the administration of these vaccines specifically to patients with chromosome 22q11.2 deletion syndrome. This syndrome is also sometimes called DiGeorge syndrome and is associated with thymic hypoplasia and diminished T-cell numbers and has a wide spectrum of phenotypic features that include cardiac anomalies, dysmorphic facial features, and hypocalcemia. Patients generally exhibit a mild to moderate decrement in T-cell numbers with preservation of T-cell function. The aims of this study were to investigate the incidence of side effects after live viral vaccine administration in a population with chromosome 22q11.2 deletion syndrome. The high frequency of this syndrome in the population (1:3000 children) mandates a greater understanding of the risks and benefits related to live viral vaccine administration. A retrospective analysis of vaccine adverse events was performed. The data acquisition form evaluated the frequency of live vaccine administration and the consequences of both vaccination and withholding the vaccine. Flow cytometric enumeration of T cells was performed as part of an immunologic evaluation. Thirty-two of 59 responders were vaccinated with the varicella vaccine. Only 9% of patients reported adverse events. However, 63% of unvaccinated children developed chickenpox. Comparison of patients who tolerated the vaccine with those who reported adverse events showed no statistically significant differences in current age (7 vs 5.7 years), age at vaccination (3 vs 2.5 years), or T-cell subset counts: CD3 (1951 vs 2083 cells/ microL), CD4 (1283 vs 1463 cells/ microL), and CD8 (530 vs 502 cells/ microL). Fifty-two of 59 responders were vaccinated with measles-mumps-rubella (MMR). Twelve (23%) of 52 reported mild side effects, including fever, rash, and constitutional symptoms. No severe adverse reactions were reported. No patient reported natural disease with measles, mumps, or rubella. There were no statistically significant differences between the T-cell counts in the vaccinated group reporting side effects versus the vaccinated group without side effects (mean CD3 counts: 1928 vs 1736 cells/ microL; CD4 counts: 1250 vs 1127 cells/ microL; and CD8 counts: 528 vs 483 cells/ microL). In our study, patients with chromosome 22q11.2 deletion syndrome had a similar incidence of adverse effects with varicella and MMR vaccines compared with that reported in the general population. All side effects were mild. However, in patients who did not receive the varicella vaccine, an overwhelming 63% contracted the disease. Patients who were not vaccinated against MMR did not develop natural disease. The data suggest that this is a cohort of patients with 22q11.2 deletion syndrome who have tolerated live viral vaccinations without evidence of significant side effects. A prospective study could address whether there are T-cell thresholds below which vaccination is unsafe; however, the information that we present suggests that vaccinating children with chromosome 22q11.2 deletion with live viral vaccines does not carry a significantly higher risk of adverse reactions compared with the general population, provided that they have no evidence of severe immunocompromise.     

Measles,mumps, rubella (vaccine) and varicella vaccines in pediatric liver transplant: An initial analysis of post‐transplant immunity

Varicella and measles infection represents a significant source of morbidity and mortality for pediatric LT recipients. We evaluated the prevalence and correlates of post‐transplant immunity in pediatric LT recipients previously immunized against measles (n = 72) and varicella (n = 67). Sixteen of seventy‐two (22%) patients were measles non‐immune, and 42/67 (63%) were varicella non‐immune after LT. Median time from LT to titers for measles and varicella was 4.0 and 3.3 years, respectively. In the measles cohort, non‐immune patients received fewer pretransplant vaccine doses (P = 0.026) and were younger at both time of vaccination (P = 0.006) and LT (P = 0.004) compared with immune patients. Upon multivariable analysis, weight > 10 kg at LT (OR 5.91, 95% CI 1.27‐27.41) and technical variant graft (OR 0.07, 95% CI 0.01‐0.37) were independently, significantly associated with measles immunity. In the varicella cohort, non‐immune patients received fewer pretransplant vaccine doses (P = 0.028), were younger at transplant (P = 0.022), and had less time lapse between their last vaccine and transplant (P = 0.012) compared with immune patients. Upon multivariate analysis, time > 1 year from last vaccine to LT was independently, significantly associated with varicella immunity (OR 3.78, CI 1.30‐11.01). This study demonstrates that non‐immunity to measles and varicella is a prevalent problem after liver transplantation in children and identifies 3 unique risk factors for non‐immunity in this high‐risk population.     

Consensus: varicella vaccination of healthy children--a challenge for Europe

The seriousness of varicella-zoster virus (VZV) infection as a public health issue is becoming clearer as country-specific epidemiologic and pharmacoeconomic data become available. In Germany, for example, studies have shown that >5.5% of immunologically healthy individuals develop varicella-related complications such as bacterial superinfections, acute neurologic disorders, pneumonia, bronchitis and otitis media; whereas in Italy, 3.5 to 5% of childhood cases of varicella cause complications such as upper respiratory tract and cutaneous infections.Varicella vaccines are now available. These live attenuated Oka strain vaccines have been shown in extensive studies to be highly immunogenic and well-tolerated in immunocompetent and immunocompromised children, with seroconversion rates ranging from 94 to 100% and 53 to 100%, respectively. These vaccines are also highly effective against clinical disease.These considerations led to a reevaluation of varicella vaccination policies. A routine varicella vaccination program targeting healthy children has already been implemented in the US, and data produced are encouraging and valuable. Similar strategies have not yet been adopted across Europe. The European Working Group on Varicella (EuroVar) was formed in 1998 to address the issues surrounding varicella epidemiology in Europe. After a series of meetings, the EuroVar members prepared a consensus statement recommending routine varicella vaccination for all healthy children between 12 and 18 months and to all susceptible children before their 13th birthday, in addition to catch-up vaccination in older children and adults who have no reliable history of varicella and who are at high risk of transmission and exposure. However, such a policy is recommended only if a very high coverage rate can be achieved. This could be reached with a measles-mumps-rubella-varicella combined vaccine.     

Szczepienia u dzieci z chorobą nowotworową − aktualne polskie zalecenia

The article presents, in accordance with current recommendations of the Infectious Diseases Society of America (IDSA) and the Programme of Immunization 2017 (PSO), proposals for the implementation of vaccination in children with cancer, depending on the applied treatment. We recommend to start vaccination 6 months after the end of cancer treatment, which is consistent with the guidelines of the IDSA. After vaccination with a live measles, mumps, rubella (Measles, Mumps, and Rubella, MMR), we recommend antibody level examination. In children treated with anti-CD20, we recommend vaccination after 6 months after completion of therapy. “Killed” vaccines can be administered 6 months after completion of cancer treatment. In the case of “live” vaccines, time of vaccination must be dependent on dose and time of administration of immunoglobulins.In children with autologous hematopoietic stem cell transplant (HSCT), we recommend vaccination at 6, and after allogeneic at 12 months after the transplant.Children after oncological treatment have an increased risk of viral and bacterial infections, particularly encapsulated bacteria; hence, be aware of vaccination against Haemophilus influenza, Streptococcus pneumoniae and Neisseria meningitidis.     

Application of a Live Varicella Vaccine to the Immunosuppressive Children and the Incibence of a Case of Herpes Zoster after Vaccination

A live varicella vaccine was applied to 13 susceptible children to varicella virus. Three were receiving steroid therapy, and one of them was treated with both steroid and anticancer drugs. Immunosuppressive therapy and anticancer medication were not suspended before and after vaccination. Serological responses were observed in 11 of 13 vaccinated children by fluorescent antibody to membrane antigen (FAMA) test 6 to 7 weeks after Vaccination. Mild rash appeared as only a clinical reaction in 3 of the vaccinated children. However, 3 and a half months later, a vaccinee with acute myeloblastic leukemia, developed herpes zoster. Our observation suggested a possibility of contracting zoster in immune compromised hosts after vaccination with a live varicella vaccine.     

Vaccination

Vaccination has been an important part of antiinfectious prophylaxis in pediatric oncology comprising immunizations with special indication like varicella vaccine and follow-up of routine immunizations after chemotherapy and bone marrow transplantation (BMT). Studies from the last decade demonstrate a loss of long term immunity to immunization preventable disease in most patients with chemotherapy and BMT who had received appropriate immunization before. So far routine vaccination programs following intensive chemotherapy have not been studied prospectively. Immunization programs following BMT have shown that immunizations with tetanus toxoid, diphtheria toxoid, inactivated poliovirus vaccine and influenza vaccine - given at least 12 months after transplantation - are safe and effective. Vaccination with live attenuated trivalent vaccine against measles, mumps and rubella in patients without chronic "graft versus host disease" (GVHD) and without ongoing immunosuppressive therapy, performed 24 months after transplantation, proved to be safe too. Recommendations have been published by 5 different official groups: (1.) "St?ndige Impfkommission" (STIKO) and (2.) "Deutsche Gesellschaft für p?diatrische Infektiologie" (DGPI) recommend varicella vaccine für children with leukemia in remission for at least 12 months, for children with solid tumors and for patients getting an organ transplantation. Both societies do not comment on the schedule of booster vaccinations (with live attenuated vaccines) after the end of chemotherapy and after BMT. (3.) "Qualit?tssicherungsgruppe" der "Gesellschaft für p?diatrische Onkologie und H?matologie" (QS-GPOH) recommends immunization with nonliving vaccines when the patient is off therapy for at least 3 months and immunization with live attenuated vaccines when he is off therapy for at least 6 months. This group does not comment on varicella vaccine which has been controversial among pediatric oncologists. (4.) The " Infectious disease working party of the European group for Blood and Marrow Transplantation" (EBMT) recommends immunization with nonliving vaccines when the patient is off transplantation for at least 12 months, without GVHD and without immunosuppressive therapy. (5.) The "Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant (HSCT) Recipients" published by the following american institutions and societies: "Centers for Disease Control and Prevention", "Infectious Diseases Society of America" and "American Society of Blood and Marrow Transplantation" recommend that patients should be routinely revaccinated after transplantation if they are off immunosuppressive therapy and do not suffer from GVHD: beginning of vaccinations with nonliving vaccines in the second year after HSCT, beginning of vaccinations with live attenuated vaccines in the third year after HSCT. Life-long seasonal influenza vaccination is recommended for all HSCT candidates and recipients, beginning during the influenza season before HSCT and resuming > 6 months after HSCT. IT would be appreciated if working groups of these societies could find consensus recommendations on open and controversial questions in the near future.     

Live viral vaccines in a DiGeorge syndrome patient

We report a case of pneumonia in a 13 month old male child with partial DiGeorge syndrome who died after inadvertently receiving live viral vaccines. Although live viral vaccines have been used safely in some children with DiGeorge syndrome, there are insufficient data to recommend their routine use in those with severe immunodeficiency.     

Live viral vaccines in a DiGeorge syndrome patient.

We report a case of pneumonia in a 13 month old male child with partial DiGeorge syndrome who died after inadvertently receiving live viral vaccines. Although live viral vaccines have been used safely in some children with DiGeorge syndrome, there are insufficient data to recommend their routine use in those with severe immunodeficiency.     

Varicella vaccination in pediatric kidney and liver transplantation

Prelog M, Zimmerhackl LB. Varicella vaccination in pediatric kidney and liver transplantation.
Pediatr Transplantation 2010: 14: 41–47. © 2009 John Wiley & Sons A/S.
Abstract:  Reports about efficacy and safety of live-virus attenuated vaccines in patients before and after transplantation are mainly based on small patient numbers, making general recommendations for this patient population difficult. Children and adults as well as their close relatives and contact persons should be preferably immune to VZV before solid organ transplantation to avoid VZV-associated complications, thus making VZV vaccination necessary in susceptible individuals. The following literature review focused on efficacy and safety of VZV vaccination in pediatric kidney and liver transplant recipients. Review of literature also revealed that in all pediatric transplant candidates, humoral and cellular immunity against VZV should be consistently monitored to assess waning immunity under immunosuppressive treatment. This approach is desirable to estimate the risk of severe varicella disease after exposure in these patients.     

Combined vaccine against measles, mumps, rubella, and varicella

A combined measles, mumps, rubella, and varicella vaccine produced seroconversions for all four components similar to that found if measles, mumps, and rubella vaccine or live varicella vaccine were given separately. In addition, those exposed to varicella were completely protected or had only a mild rash. Moreover, the reaction rates were not increased if the vaccines were combined. The somewhat lower and delayed serologic response to live varicella vaccine as compared with the combined measles, mumps, rubella, and varicella may have been due to the small amount of varicella vaccine virus used or to its degree of attenuation. Persistence of antibody was observed 1 year postimmunization.     

Vaccinations,response, and controls before and after intestinal transplantation in children

Vaccination is an effective strategy to decrease infections in transplant recipients. Children after intestinal transplantation carry a high risk of infection due to increased immunosuppression. In a series of 22 children after intestinal transplantation, we studied the vaccination schedules and the antibodies against vaccine‐preventable diseases before transplantation, and at one and five yr after transplantation. We reviewed whether the vaccination schedules were complete, and we analysed the factors that may influence serological immunity and the incidence of disease in patients with deficient immunity. All patients completed the recommended vaccination schedules for DTaP‐IPV and HBV. After transplantation, the negative antibodies against vaccine‐preventable diseases were mostly related to an antirejection therapy: for DTaP‐IPV: four of four patients with no antibody had been treated for rejection, for HBV: two of five, HAV: three of four, MMR: three of seven, and VZV: three of four. A post‐transplantation varicella infection was followed by acute rejection, with probability for a relationship between both events. We observed 50% of varicella cases in unvaccinated children, highlighting the importance of pretransplant vaccination. Waning immunogenicity mediated by antibodies against vaccine‐preventable disease after transplantation indicated a need for boosters. The recommendations should be regularly enforced, as the reliance on routine immunizations schedules is not adequate in immunocompromised patients.     

腺苷脱氨酶缺陷重症联合免疫缺陷伴疫苗接种后播散性水痘感染一例

目的 提高对腺苷脱氨酶(ADA)缺陷重症联合免疫缺陷(SCID)及疫苗接种后播散性水痘感染的认识.方法 结合1例ADA缺陷SCID伴疫苗接种后播散性水痘感染的临床资料和文献复习,探讨ADA缺陷SCID背景知识、临床表现、诊断和治疗.结果 患儿存在生长停滞情况,以发热、皮疹3周余入院,出皮疹前两周曾接种水痘疫苗,水痘直接免疫荧光试验阳性,血液常规检查淋巴细胞比例和绝对值(105×106/L)明显降低,IgG(1520 ms/L)、IgM(250 mg/L)和IgA(102 ms/L)显著降低,淋巴细胞亚群CD3、CD4、CD8和CD19的相对比例和绝对值均显著降低,CD56比例升高,但其绝对值显著降低.红细胞ADA值明显降低,脱氧核苷酸腺苷明显升高.结论 ADA缺陷SCID存在特征性改变,目前的治疗方法包括造血干细胞移植、酶替代治疗和基因治疗.对生长发育停滞儿童需重视免疫功能评估,对免疫缺陷病患儿需加强疫苗接种管理.     

Variability in immunization guidelines in children before and after lung transplantation

Lung transplant candidates and recipients are at high risk of infections from vaccine-preventable diseases. However, well-established guidelines neither exist for pre- and post-transplant vaccination nor do monitoring guidelines for pediatric lung transplant recipients. To ascertain the current vaccination and monitoring practices of pediatric lung transplant centers, a self-administered questionnaire was distributed to the 18 pediatric lung transplant centers within the International Pediatric Lung Transplant Collaborative in April 2006. Sixteen of 18 centers (89%) surveyed responded. Pretransplant, national vaccination guidelines are followed. Eleven centers reported following standardized vaccination guidelines post-transplant. Vaccines were more commonly provided by the primary-care physician pretransplant (69%) rather than post-transplant (38%). Post-transplant, 50% of the centers recommend live vaccines for household contacts but not for the transplant recipient. Pretransplant monitoring of response to prior vaccination was performed inconsistently except for varicella (88%). Only 44% of the transplant centers measure for response to vaccination post-transplant, mostly hepatitis B. Current vaccination practices of pediatric lung transplant centers are heterogeneous. The lung transplant community would be well served by studies designed to evaluate the efficacy of vaccinations in this population.     

Viral strain identification in varicella vaccinees with disseminated rashes

BACKGROUND: Approximately 15% of recipients of live attenuated varicella vaccine may develop mild breakthrough varicella months to years after immunization. Although some vaccinees will develop zoster, it is less common in recipients of vaccine than in those who have had natural varicella. OBJECTIVE: To determine the varicella-zoster virus (VZV) strain responsible for breakthrough varicella and zoster in recipients of varicella vaccine. METHODS: A PCR assay capable of distinguishing wild-type from vaccine strain VZV was performed on samples from skin lesions from vaccinees with breakthrough varicella and zoster. RESULTS: All of 57 vaccinees with breakthrough varicella, clinically diagnosed on the basis of a generalized maculopapular or vesicular rash, in which there was amplifiable DNA [corrected], had wild-type VZV infection based on analysis of viral DNA. The Oka vaccine strain of VZV was not identified in any of these cases. In contrast, in 32 patients with zosteriform rashes, the vaccine strain was identified in 22 samples, and the wild-type strain was identified in 10 samples. CONCLUSIONS: Wild-type virus was identified in all generalized rashes occurring after the immediate 6-week postvaccination period. When reactivation of vaccine strain occurred, it presented as typical zoster. We find no evidence that reactivation of vaccine virus occurs with the clinical picture of generalized rash.     

Impact of a pharmacist‐led vaccine recommendation program for pediatric kidney transplant candidates

Pediatric transplant recipients commonly have deficient vaccination status at the time of transplantation. Utilizing transplant pharmacists to improve vaccination rates has not previously been described. This single‐center, retrospective study evaluated the impact of transplant pharmacist interventions on the completion rate of vaccination schedules at time of kidney transplant. Patients who received pharmacist‐led vaccination recommendations prior to transplant were compared to patients without pharmacist recommendations. Forty‐seven pediatric patients were included: 24 intervention patients and 23 control patients. The median percentage of up‐to‐date vaccinations at time of transplant was significantly higher in intervention group (91%; IQR 86%‐100%) vs. control group (80%; IQR 71%‐80%) (P<.0001). The median change in up‐to‐date vaccinations from time of evaluation to time of transplant was also significantly higher in the intervention group (7.5%) compared to the control group (0%) (P<.0001). There was no difference in live vaccination rates. No patients in either group were readmitted for a vaccine‐preventable disease within 6 months post‐transplant. With pharmacist intervention, significantly more patients were up to date with vaccination schedules at the time of transplant. These results suggest that a transplant pharmacist may serve as a valuable resource to increase vaccination schedule compliance between time of evaluation and transplantation.     

Immunization of HIV-infected children with varicella vaccine

OBJECTIVE: To determine the safety and immunogenicity of varicella vaccine in children with human immunodeficiency virus (HIV) infection. Children (n = 41) who were mildly affected by HIV (Centers for Disease Control and Prevention stage N1 or A1) and had no history or serum antibody indicative of prior varicella infection were immunized with two doses of live attenuated varicella vaccine. RESULTS: A minority of the vaccine recipients had mild local or systemic reactions. Vaccination had no effect on the clinical stage of HIV or the HIV RNA plasma load. CD4 cell percentage and CD4 cell count were marginally decreased at week 4 after the first vaccination; this effect was no longer present at week 8 after vaccination. Two months after the second dose of vaccine, 60% of vaccine recipients had anti-varicella antibody in their serum, and 83% had a positive lymphocyte proliferation assay response to varicella antigen. CONCLUSION: On the basis of its safety and immunogenicity, varicella vaccine should be considered in the childhood vaccines given to mildly affected HIV-infected children.     

Immunogenicity of a prophylactic quadrivalent human papillomavirus L1 virus‐like particle vaccine in male and female adolescent transplant recipients

Organ TX recipients are at an increased risk of developing cancers of the lower genital tract related to HPV. The quadrivalent HPV vaccine has high efficacy in preventing these diseases, but response to many vaccines is suboptimal after organ transplantation. Liver and kidney TX recipients received quadrivalent HPV vaccine. Serum samples were tested for anti‐HPV levels. Of 20 renal transplant recipients screened, 14 received vaccine. Of these, seven completed the vaccine series and seven had incomplete vaccination. Of five liver TX children, three received vaccines (two complete and one incomplete). All eight kidney and liver TX children with complete vaccination and available results were seronegative at baseline and had seroconversion at month 7 for all four HPV types. Six of 14 (42.8%) kidney TX recipients developed AR. During the same time period, eight of 28 (28.5%) non‐vaccine renal transplant recipients developed AR (p = ns). Transplant adolescents developed 100% seroconversion to all four HPV serotypes with HPV vaccine with serologic titers similar to historic controls. A non‐significant increased incidence of AR was noted among kidney transplant vaccine recipients. A much larger study would be needed to evaluate whether HPV vaccination increases AR in transplant adolescents.