Vaccination With Heterologous HIV-1 Envelope Sequences and Heterologous Adenovirus Vectors Increases T-Cell Responses to Conserved Regions: HVTN 083.

BACKGROUND: Increasing the breadth of human immunodeficiency virus type 1 (HIV-1) vaccine-elicited immune responses or targeting conserved regions may improve coverage of circulating strains. HIV Vaccine Trials Network 083 tested whether cellular immune responses with these features are induced by prime-boost strategies, using heterologous vectors, heterologous inserts, or a combination of both. METHODS: A total of 180 participants were randomly assigned to receive combinations of adenovirus vectors (Ad5 or Ad35) and HIV-1 envelope (Env) gene inserts (clade A or B) in a prime-boost regimen. RESULTS: T-cell responses to heterologous and homologous insert regimens targeted a similar number of epitopes (ratio of means, 1.0; 95% confidence interval [CI], .6-1.6; P = .91), but heterologous insert regimens induced significantly more epitopes that were shared between EnvA and EnvB than homologous insert regimens (ratio of means, 2.7; 95% CI, 1.2-5.7; P = .01). Participants in the heterologous versus homologous insert groups had T-cell responses that targeted epitopes with greater evolutionary conservation (mean entropy [±SD], 0.32 ± 0.1 bits; P = .003), and epitopes recognized by responders provided higher coverage (49%; P = .035). Heterologous vector regimens had higher numbers of total, EnvA, and EnvB epitopes than homologous vector regimens (P = .02, .044, and .045, respectively). CONCLUSIONS: These data demonstrate that vaccination with heterologous insert prime boosting increased T-cell responses to shared epitopes, while heterologous vector prime boosting increased the number of T-cell epitopes recognized. CLINICAL TRIALS REGISTRATION: NCT01095224.

Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial.

BACKGROUND: Modified vaccinia Ankara (MVA-BN, IMVAMUNE) is emerging as a primary immunogen and as a delivery system to treat or prevent a wide range of diseases. Defining the safety and immunogenicity of MVA-BN in key populations is therefore important. METHODS: We performed a dose-escalation study of MVA-BN administered subcutaneously in 2 doses, one on day 0 and another on day 28. Twenty-four hematopoietic stem cell transplant recipients were enrolled sequentially into the study, and vaccine or placebo was administered under a randomized, double-blind allocation. Ten subjects received vaccine containing 10(7) median tissue culture infective doses (TCID50) of MVA-BN, 10 subjects received vaccine containing 10(8) TCID50 of MVA-BN, and 4 subjects received placebo. RESULTS: MVA-BN was generally well tolerated at both doses. No vaccine-related serious adverse events were identified. Transient local reactogenicity was more frequently seen at the higher dose. Neutralizing antibodies (NAb) to Vaccinia virus (VACV) were elicited by both doses of MVA-BN and were greater for the higher dose. Median peak anti-VACV NAb titers were 1:49 in the lower-dose group and 1:118 in the higher-dose group. T-cell immune responses to VACV were detected by an interferon γ enzyme-linked immunosorbent spot assay and were higher in the higher-dose group. CONCLUSIONS: MVA-BN is safe, well tolerated, and immunogenic in HSCT recipients. These data support the use of 10(8) TCID50 of MVA-BN in this population. CLINICAL TRIALS REGISTRATION: NCT00565929.

From the Medical Board of the National Psoriasis Foundation: Vaccination in adult patients on systemic therapy for psoriasis.

Patients with moderate to severe psoriasis often require systemic immunomodulatory medications that place them at risk for infection. Vaccination is a proven strategy to reduce infections. However, vaccination rates among patients with inflammatory autoimmune conditions, including psoriasis, remain low. We review the literature regarding vaccine-preventable illness and vaccinations commonly used in the United States in patients older than 18 years on immunosuppressive therapies that are used in the treatment of psoriasis. The medical board of the National Psoriasis Foundation recommends that dermatologists counsel patients on updating vaccinations in accordance with recommendations of the Advisory Committee for Immunization Practices as any measures taken to prevent infection can increase the safety of immunomodulatory therapies.

Demonstration of durable hepatitis B immune memory in children vaccinated with a DTaP5-IPV-HepB-Hib infant-toddler series 7 to 8 years previously.

Vaccination against hepatitis B (HepB) provides long-term protection against infection. This is despite a reduction in HepB surface antibody (anti-HBs) concentrations over time to levels below the well-accepted correlate of protection of ≥10 mIU/mL. Continued evidence of immune memory and protection despite declined anti-HBs concentrations can be demonstrated by HepB virus surface antigen challenge studies. Long-term immune memory and protection against HepB infection has not been demonstrated previously for the pediatric hexavalent vaccine DTaP5-IPV-HepB-Hib. This phase 3, multicenter, single-group, open-label challenge study (NCT04490499; EudraCT: 2020-000126-26) evaluated immune memory against HepB infection in children who had received DTaP5-IPV-HepB-Hib at 2, 4, and 11-12 months of age, or at 2, 3, 4, and 12 months of age. At age 8-9 years, they were each challenged with 5 µg of monovalent HepB vaccine. Anti-HBs levels were measured on pre-challenge day 1 and post-challenge day 30. At baseline, 45.4% (93 of 205) had anti-HBs levels ≥10 mIU/mL. On post-challenge day 30, 99.5% (201 of 202) had anti-HBs levels ≥10 mIU/mL, regardless of initial vaccination schedule. Post-challenge, geometric mean concentrations increased 71-fold over baseline and 96.0% of children had a ≥4-fold rise in anti-HBs concentrations with similar results across both dosing schedules. The challenge dose was well tolerated. The robust anti-HBs responses after a single 5-µg dose of HepB vaccine confirm the persistence of a HepB immune memory and demonstrate that DTaP5-IPV-HepB-Hib provides long-term protection against HepB.

Effect of vaccination with modified vaccinia Ankara (ACAM3000) on subsequent challenge with Dryvax.

BACKGROUND: Despite the success of smallpox vaccination, the immunological correlates of protection are not fully understood. To investigate this question, we examined the effect of immunization with modified vaccinia Ankara (MVA) on subsequent challenge with replication-competent vaccinia virus (Dryvax). METHODS: Dryvax challenge by scarification was conducted in 36 healthy subjects who had received MVA (n = 29) or placebo (n = 7) in a previous study of doses and routes of immunization. Subjects were followed up for clinical take, viral shedding, and immune responses. RESULTS: MVA administration attenuated clinical takes in 21 (72%) of 29 subjects, compared with 0 of 7 placebo recipients (P = .001). Attenuation was most significant in MVA groups that received 1 x 10(7) median tissue culture infective doses (TCID(50)) intradermally (P = .001) and 1 x 10(7) TCID(50) intramuscularly (P = .001). Both duration and peak titer of viral shedding were reduced in MVA recipients. Peak neutralizing antibody responses to vaccinia virus or MVA previously induced by MVA immunization were associated with attenuated takes (P = .02) and reduced duration (P = .001) and titer (P = .005) of viral shedding. CONCLUSIONS: MVA immunization results in clinical and virologic protection against Dryvax challenge. Protection is associated with prior induction of neutralizing antibodies to MVA or vaccinia virus. MVA administered intradermally has protective and immunologic responses similar to those of a 10-fold-higher dose given subcutaneously.

Safety and immunogenicity of modified vaccinia Ankara (ACAM3000): effect of dose and route of administration.

BACKGROUND: We conducted a clinical trial of the safety and immunogenicity of modified vaccinia Ankara (MVA) to examine the effects of dose and route of administration. METHODS: Seventy-two healthy, vaccinia virus-naive subjects received 1 of 6 regimens of MVA (ACAM3000) or placebo consisting of 2 administrations given 1 month apart. RESULTS: MVA was generally well tolerated at all dose levels and by all routes. More pronounced local reactogenicity was seen with the intradermal and subcutaneous routes than with intramuscular administration. Binding antibodies to whole virus and neutralizing antibodies to the intracellular mature virion and extracellular enveloped virion forms of vaccinia virus were elicited by all routes of MVA administration and were greater for the higher dose by each route. Similar levels of neutralizing antibodies were seen at a 10-fold-lower dose given intradermally (1 x 10(7) median tissue culture infective doses [TCID(50)]), compared with responses after 1 x 10(8) TCID(50) given intramuscularly or subcutaneously. T cell immune responses to vaccinia virus were detected by an interferon gamma enzyme-linked immunospot assay but had no clear relationship to dose or route. CONCLUSIONS: These data suggest that intradermal immunization with MVA provides a dose-sparing effect by eliciting antibody responses similar in magnitude and kinetics to those elicited by the intramuscular or subcutaneous routes but at a 10-fold-lower dose.

Protective immune responses against Haemophilus influenza type b elicited by a fully-liquid DTaP-IPV-Hib-HepB vaccine (VAXELIS™).

BACKGROUND: DTaP-IPV-Hib-HepB is a fully-liquid, hexavalent combination vaccine (Vaxelis™) approved for vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzae type b (Hib). Hib capsular polysaccharide, polyribosylribitol phosphate (PRP), is conjugated to Neisseria meningitidis outer membrane protein complex (OMPC). Safety and immunogenicity of DTaP-IPV-Hib-HepB were evaluated in 6 Phase III clinical studies including > 5,200 children. Studies included vaccination schedules in the United States (2, 4, 6 months of age) and Europe (2, 3, 4, 12 months of age and 2,4,11-12 months of age). METHODS: Data pertaining to anti-PRP responses of DTaP-IPV-Hib-Hep B compared to control vaccines from 5 Phase III studies are summarized. RESULTS: Post-infant series, the percentage of participants that achieved protective antibody thresholds for PRP (anti-PRP titer ≥ 0.15 µg/mL and ≥ 1.0 µg/mL, respectively) were higher in DTaP-IPV-Hib-HepB recipients compared to recipients who received control vaccines. A high level of protective responses (96.6% at ≥ 0.15 µg/mL [95% CI:94.8, 97.9%]; 72.9% at ≥ 1.0 µg/mL [95% CI:69.2,76.4%]) were seen post-dose 2 of the 2 + 1 vaccination schedule and met superiority criteria over comparator, p-value < 0.001. In the same schedule, prior to administration of the toddler dose (in the second year of life), anti-PRP titers were higher in DTaP-IPV-Hib-HepB recipients (91.4% at ≥ 0.15 µg/mL; 46.8% at ≥ 1.0 µg/mL) as compared to recipients who received control vaccines (63.4% at ≥ 0.15 µg/mL; 17.1% at ≥ 1.0 µg/mL). One-month post-toddler dose, high levels of anti-PRP titers were achieved in both DTaP-IPV-Hib-HepB recipients (99.8% at ≥ 0.15 µg/mL; 96.6% at ≥ 1.0 µg/mL) and recipients who received control vaccines (99.5% at ≥ 0.15 µg/mL; 94.9% at ≥ 1.0 µg/mL). CONCLUSIONS: These results support that DTaP-IPV-Hib-HepB induces a robust and sustained early Hib response. During the high-risk period for Hib disease after the infant vaccine and prior to the toddler dose; >90% of recipients maintained superior protective anti-PRP levels compared to control.

Safety and immunogenicity of a fully-liquid DTaP-IPV-Hib-HepB vaccine (Vaxelis™) in premature infants.

Background: Immune immaturity may put premature infants at increased risk for infections. DTaP-IPV-Hib-HepB vaccine (Vaxelis™), a hexavalent vaccine studied in >6,800 children, has acceptable safety and immunogenicity profiles generally similar to control vaccines. Here we evaluate safety and immunogenicity of DTaP-IPV-Hib-HepB vaccine in premature infants. Methods: Premature infants were identified using prior medical conditions terms "premature baby/delivery" and/or "low birth weight baby". Immunogenicity and safety data were summarized across one Phase II and four Phase III randomized, active-comparator-controlled clinical trials (Protocol 004 in Canada [Control: PENTACEL™]; Protocols 005 and 006 in the US [Control: PENTACEL™]; and Protocols 007 and 008 in the EU [Control: INFANRIX™ hexa]) and one Phase III clinical trial in the UK (PRI01C); no formal statistical comparisons were performed. Results: Overall, 160 infants were considered premature (DTaP-IPV-Hib-HepB = 111 Control = 49). The incidence of adverse events (AEs) for DTaP-IPV-Hib-HepB was comparable between overall and premature populations for all AEs days 1-15 postvaccination (Overall = 96.3%; Premature = 97.3%;), solicited injection-site AEs days 1-5 postvaccination (Overall = 84.1%; Premature = 75.5%), and solicited systemic AEs days 1-5 postvaccination (Overall = 93.7%; Premature = 94.5%). A high percentage of premature infants mounted protective immune responses to antigens contained in DTaP-IPV-Hib-HepB vaccine. Response rates in preterm infants for all antigens (80-99%) were in a similar range to all infants (80-99%) for both DTaP-IPV-Hib-HepB and control vaccines. Conclusions: DTaP-IPV-Hib-HepB vaccine has a low incidence of AEs, an acceptable safety profile, and elicited satisfactory immune responses in premature infants comparable to the overall study population. These findings support vaccination with DTaP-IPV-Hib-HepB vaccine in healthy premature infants.

Vaccination after stem cell transplant: a review of recent developments and implications for current practice.

PURPOSE OF REVIEW: We have seen significant advances in the fields of stem cell transplantation and vaccinology. However, vaccination practices after transplantation remain varied and data sparse. We review recent changes in adult stem cell transplantation that pertain to vaccination practice, and discuss the evidence guiding the use of established and newly approved vaccines. RECENT FINDINGS: Infection remains an important cause of morbidity and mortality in the stem cell transplant population. To extend stem cell transplantation to an increased number of patients and to widen the sources of donor cells, nonmyeloablative stem cell transplantation and cord blood transplantation have been used with increased frequency. These newer modalities differ in their immunological deficits, risk of infection and response to vaccination. Alternate vaccination regimens such as vaccination of either donors or recipients or both prior to stem cell harvest and early repeated vaccination after transplantation have been investigated. The full utility of these methods has yet to be delineated. The safety and benefit of new vaccines such as the acellular pertussis, human papilloma virus or varicella virus vaccine have yet to be formally investigated. We would argue that their use may be appropriate in the right setting. SUMMARY: The complexity of stem cell transplantation continues to evolve and so must vaccine practices in this population. New vaccines that have the potential to improve long-term outcome should be investigated.

A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Cytomegalovirus reactivation occurs within 6 months in 60-70% of cytomegalovirus-seropositive patients after allogeneic haemopoietic stem-cell transplantation (HSCT), mainly due to immunosuppression associated with the procedure. Pre-emptive antiviral therapy reduces incidence of cytomegalovirus disease but can be toxic. To reduce the potential for disease and subsequent need for such antiviral drugs, we aimed to assess safety and efficacy of a cytomegalovirus therapeutic DNA vaccine compared with placebo. METHODS: In this exploratory double-blind, placebo-controlled, parallel group, phase 2 trial, up to 80 donor-recipient pairs and 80 unpaired recipients undergoing allogeneic HSCT were planned for enrolment at 16 transplant centres in the USA. Eligible recipients were cytomegalovirus-seropositive, 18-65 years old, without high-risk primary disease, T-cell depletion, previous vaccination for cytomegalovirus, or autoimmune diseases. We randomly allocated participants in both parallel groups in a 1:1 ratio to receive a cytomegalovirus therapeutic DNA vaccine (TransVax; Vical, San Diego, CA, USA) or placebo before conditioning and at 1, 3, and 6 months after transplantation. The vaccine contains plasmids encoding cytomegalovirus glycoprotein B and phosphoprotein 65 formulated with poloxamer CRL1005 and benzalkonium chloride. Randomisation was done by sequential allocation based on Pocock and Simon's method, and stratified by site, donor-recipient HLA matching status, and donor's cytomegalovirus serostatus. The primary outcome was the occurrence rate of clinically significant viraemia resulting in initiation of cytomegalovirus-specific antiviral therapy in the per-protocol assessable population. We assessed rates of adverse events in all participants who received at least one dose of vaccine or placebo. This study is registered with ClinicalTrials.gov, number NCT00285259. FINDINGS: We randomly allocated 108 participants (94 HSCT recipients and 14 paired donors) between June 29, 2006, and Dec 11, 2009. Enrolment of the paired arm was halted in February 2008 for logistical reasons. Safety was assessed in all participants; the efficacy population was restricted to 74 unpaired recipients. Groups were balanced for demographic and clinical variables. 19 (48%) of 40 vaccine recipients required cytomegalovirus-specific antiviral therapy, compared with 21 (62%) of 34 controls (p=0·145). However, during follow-up vaccine significantly reduced the occurrence and recurrence of cytomegalovirus viraemia and improved the time-to-event for viraemia episodes compared with placebo. The vaccine was well-tolerated; only one participant discontinued after an allergic reaction. Incidence of common adverse events after HSCT (eg, graft-versus-host disease or secondary infections) did not differ between groups. INTERPRETATION: We show proof of concept for an immunotherapeutic cytomegalovirus vaccine (TransVax) for clinically significant viraemia in the HSCT setting. The reported safety and efficacy outcomes support further development in a phase 3 trial, notwithstanding a lack of significant reduction in the use of cytomegalovirus-specific antiviral therapy compared with placebo in this phase 2 trial. FUNDING: Vical and US National Institute of Allergy and Infectious Diseases.