A Phase 4 interventional study of TicoVac in Tick-Borne Encephalitis, sponsored by University of Surrey. Completed at 1 site in United Kingdom. Open to female participants aged 18 Years to 49 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-08-03.
Sponsored by University of Surrey · Phase 4, Interventional, and Treatment
Many viral infections of global importance, including HIV, are transmitted across the mucosal surface of the genital tract. As immunity against these infections is likely to be primarily mediated by antibodies in mucosal secretions, developing techniques to increase the levels and persistence of antiviral antibody on mucosal surfaces may enhance the protection against a number of important infections. Preclinical studies have anatomically targeted vaccine antigens to sites where genital tract immunity is induced. This response is likely due to the ability of regional lymph Preclinical studies have anatomically targeted vaccine antigens to sites where genital tract immunity is induced. This response is likely due to the ability of regional lymph nodes to "pattern" the cell surface markers of responding vaccine specific lymphocytes with homing markers. In contrast, injecting a distant muscle (such as in the arm) which shares no anatomical relationship with the vagina, may not pattern cells with homing markers for the genital tract. Direct injection of inguinal lymph nodes is impractical in humans but intramuscular injection into the thigh will target antigens to the deep inguinal lymph nodes shared in common with the cervix/vagina.
This study will be a Phase IV randomised, single centre, open label, laboratory assessment blinded exploratory trial to assess mucosal immunogenicity following three targeted intramuscular immunisations with TicoVac vaccine. 20 subjects will be randomised to each of2 groups immunised in right deltoid or right anterolateral thigh.
Following an initial screening visit subjects will be immunised at 0, 1 and 6 months. There will be follow up visits 5 days after each immunisation and a final visit at 7 months. Blood samples and cervicovaginal secretions will be taken prior to each immunisation for immunological measures. In addition, blood samples will be taken at each immunisation and follow up visit for measurement of peripheral blood mononuclear cells.
The study is funded by ADITEC, which is a collaborative research programme that aims to accelerate the development of novel and powerful immunisation technologies for the next generation of human vaccines.
The study will investigate whether targeting vaccine antigens to lymph nodes (internal iliac) which drain both the lower limb and the cervix/vagina alters the subsequent antibody response detected in the cervix/vagina, when compared with targeting vaccine antigens to unrelated lymph nodes such as those in the axilla that drain the right deltoid muscle of upper arm.
The right arm has been specifically selected as lymphatics in the right upper part of the body drains directly into the blood stream via the right lymphatic duct with no shared lymphatic connections to the rest of the body. In contrast lymph from the rest of the body ultimately drains into the thoracic duct (see figure below). By immunising the right arm the investigators can be sure that vaccine antigens and antigen presenting cells and activated lymphocytes will not pass through any lymph nodes in common with the cervix or vagina. In contrast by injecting the anterolateral thigh (right side selected for uniformity) the investigators can be sure that vaccine antigens will pass through the external inguinal lymph nodes which will also receive antigens and lymphocytes responding to vaginal or cervical infection or inflammation. The choice of right leg is just to standardise.
It is the investigators hypothesis therefore that as a result of antigen presentation and stimulation within a specifically "genital tract milieu" T \&B lymphocytes leaving the external iliac nodes as a result of an immunisation into the thigh will be patterned in such a way as to more likely home back to the cervix and vagina due to the common drainage of the cervix, vagina and thigh (Figure 1) into the external iliac and lateral aortic lymph nodes. In contrast, cells leaving the axillary lymph nodes after immunisation of the right arm will enter the blood directly via the right lymphatic duct and so will not pass through any lymph nodes in common with the cervix and vagina.
The investigators will detect an effect of targeted immunisation in a number of ways:
By detecting increased levels of vaccine-specific antibodies in cervico-vaginal secretions as a result of more activated B cells (plasmablasts) homing back to the genital tract. IgG antibodies may be transudated from the blood but local mucosal IgG may also be produced. In contrast, mucosal IgA is most likely to be locally produced and may therefore be preferentially affected by targeted immunisation. However as individual levels of mucosal antibody vary widely between subjects, especially with IgA, the investigators will set primary endpoints on the basis of a fold-increase in antibody levels from baseline, rather than concentration. As mucosal IgG responses are generally more reliable and of greater magnitude the investigators have set the primary objective as vaccine-specific mucosal IgG after all three immunisations. Vaccine-specific mucosal IgA responses after all three immunisations are the secondary objective. The study has been powered on the basis of the investigators limited experience with similar vaccines to detect a doubling of proportions of responders for IgG and IgA. The investigators have based the fold-increase in vaccine-specific mucosal IgG and IgA on the investigators limited experience with a similar vaccine injected into the arm(7).
In addition, the investigators will measure changes in other variables that are exploratory in nature as assays and quantification are less well established:
There will be two treatment groups:
To ensure complete disconnection of draining lymph nodes it will always be the RIGHT arm or RIGHT leg that is immunised.
It is hypothesised that targeting the internal iliac nodes will lead to an enhanced mucosal antibody response in the cervix/vagina, which will be detected by increased vaccine-specific IgA in cervico-vaginal secretions collected in a Softcup. In addition, lymphocytes (B and T cells) from external iliac lymph nodes may carry surface markers associated with mucosal homing and secrete different combinations of cytokines (Th17) than those emanating from axillary nodes which will express a systemic phenotype. This can be detected by flow cytometry, ELISPOT after bead separation using phenotypic markers, and other immunological assays.
Immune response readouts will be IgG and IgA antibodies against the TBEV antigens in the vaccine, comparing the two groups at the time point when the peak response is expected (28 days after third immunisation).
As the investigators wish to investigate the ability of the vaccine to specifically prime subjects in a targeted way, participants must be naive to the vaccine antigens and so must not have had the vaccine or TBEV infection before. Therefore the investigators will use TicoVac - a TBEV vaccine licenced in the UK that UK adults have not generally received, as TBEV infection is not endemic in the UK. TicoVac is widely used in central and eastern Europe where TBEV is endemic but extremely uncommon, and is offered to travellers from UK to endemic areas who are likely to engage in high risk activity (hiking, trekking).
Mucosal responses against TBEV are not relevant as TBEV is transmitted by tick bites. Immune responses to TicoVac will act as a model for other vaccines in which the mucosal antibody response in the vagina is of relevance to block infection (e.g. HIV, HPV, HSV) and in which targeted immunisation may increase efficacy.
Although strictly speaking the induction of anti-TBEV antibodies in cervico-vaginal secretions is of no relevance to the efficacy of the TicoVac vaccine against a blood-injected virus, the investigators have designated them as parameters of efficacy in this model of targeted immunisation.
The purpose of this human immune physiology study is to use TBEV vaccine as a model neoantigen to investigate immune readouts after antigen targeting. The collection of adverse event or safety data is therefore not relevant to the study objectives and there will be no systematic collection of safety data, other than those required for a Risk Assessed "Type A" CTIMP (SUSAR reporting to MHRA/REC/Concerned Investigators, Annual List of Suspected Serious Adverse Reactions as part of the Annual Safety Report/Development Safety Update Report).
51 studies on the registry are indexed under Encephalitis, Tick-Borne; 9 are open to participants now.
This study's enrollment of 40 is below the median of 192 across 32 interventional studies indexed under Encephalitis, Tick-Borne.
Browse Encephalitis, Tick-Borne studies →University of Surrey is the lead sponsor of 91 studies on the registry; 14 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion criteria
Any medications that are not listed in Appendix 1,or any over-the-counter treatments are not excluded.
Receipt of vaccines other than TBEV vaccines is not excluded. If other injectable vaccines are to be given during the study period, administration should preferably be into different limbs from the study vaccine.
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Autoimmune disease
A condition in which the immune system attacks the body’s own tissues, such as rheumatoid arthritis, lupus, psoriasis, type 1 diabetes or inflammatory bowel disease.
Immunotherapy studies often leave out active autoimmune disease, and some name exceptions, such as thyroid disease on replacement hormone. Check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
IM immunisation right deltoid muscle
Drug: TicoVac
IM: right upper anterolateral thigh
Drug: TicoVac
Intramuscular immunisation to right deltoid muscle (Group 1) or right upper anterolateral thigh muscle (Group 2).
Primary: Proportion of subjects with a 15-fold or greater increase from pre-immunisation levels of anti-TBEV IgG in cervico-vaginal secretions at 28 days after final immunisation.
To determine whether immunisations in the anterolateral right thigh increases the proportion of subjects with a 15-fold or greater increase from pre-immunisation levels of anti-TBEV IgG in cervico-vaginal secretions at 28 days after final immunisation when compared with immunisations in the right arm
Time frame: 28 weeks
Secondary: Proportion of subjects with a 2-fold or greater increase from pre-immunisation levels of anti-TBEV IgA in cervico-vaginal secretions at 28 days after final immunisation
To determine whether immunisations in the anterolateral right thigh increases the proportion of subjects with a 2-fold or greater increase from pre-immunisation levels of anti-TBEV IgA in cervico-vaginal secretions at 28 days after final immunisation when compared with immunisations in the right arm
Time frame: 28 weeks
This study is completed, as verified in Aug 2018. You cannot join it, but the record below documents what was studied.
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University of Surrey