SUMMARY NOTIFICATION INFORMATION FORMATSUMMARY NOTIFICATION INFORMATION FORMAT A. General...

SUMMARY NOTIFICATION INFORMATION FORMAT A. General information 1. Details of notification

(a) Member State of notification Spain (b) Notification number B/ES/18/27 (c) Date of acknowledgement of notification 18/01/2019 (d) Title of the project

A Randomized, Observer-blind, Phase 1/2a Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of Ad26.RSV.preF in RSV-Seronegative Toddlers 12 to 24 Months of Age

(e) Proposed period of release From 01/04/2019 until 01/10/2021 2. Notifier

Name of institution or company: … Janssen Vaccines & Prevention B.V. Archimedesweg 4-6 2333CP Leiden, The Netherlands 3. GMO characterization:

The Genetically Modified Organism (GMO) is denoted as Ad26.RSV.preF throughout this document. Ad26.RSV.preF is a replication-incompetent Adenovirus (human Adenovirus type 26) based vector encoding the Respiratory Syncytial Virus (RSV) Fusion (F) protein stabilized in a prefusion conformation.

(a) Indicate whether the GMO is a: viroid (.) RNA virus (.) DNA virus (x) Ad26 vector, recombinant replication-incompetent vector bacterium (.) fungus (.) animal

- mammals (.) - insect (.) - fish (.) - other animal (.)

specify phylum, class …

(b) Identity of the GMO (genus and species)

The identity of the GMO is Ad26.RSV.preF and is a replication incompetent adenovirus vector containing the sequence for the RSV Fusion (F) protein stabilized in a prefusion

2001/18/EC Directive Summary Notification Information Format Ad26.RSV.preF SPAIN

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conformation. The Ad26.RSV.preF vector is derived from the human Adenovirus group D type 26 (genus Mastadenoviridae.).

(c) Genetic stability – according to Annex IIIa, II, A(10) After administration of Ad26.RSV.preF to the subjects of the clinical trial, it will remain epichromosomal in the host cells, thus avoiding the risk of integration of the viral DNA into the host genome. In addition, as Ad26.RSV.preF is replication incompetent, it is not able to replicate its genome and can therefore be considered to be genetically stable and alterations in the genome are not expected. During the production process virus seed lots are extensively tested and characterized, which includes sequence analysis; also virus lots are subjected to sequence analysis. The Ad26.RSV.preF vector has been made replication-incompetent by removing the E1 region of the Adenovirus type 26 genome, which is required for replication. A large portion of the E3 region, which promotes persistence within the host cell, has also been removed to create sufficient space in the viral genome for insertion of foreign antigens [1]. For productive infection and replication during manufacturing, the E1 defect is supplemented by engineered E1-(from Ad5) complementing cell lines(PER.C6®) [2]. Due to the absence of any DNA sequence overlap between the Ad26 adenoviral vector and the PER.C6® cell line, the formation of RCA is prevented which is confirmed by specific safety testing (RCA test). The RCA test is reported as “no RCA detected” if it complies with the acceptance criterion of <1 RCA per 3×1010 vp. This test is required according to Ph. Eur. 5.14 and FDA 2010 guidance. The acceptance criterion of <1 RCA per 3×1010 VP is based on FDA Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC). Janssen Vaccines and Prevention B.V.

4. Is the same GMO release planned elsewhere in the Community (in conformity with Article 6(1)), by the same notifier?

Yes (x) No (.) If yes, insert the country code(s) BE 5. Has the same GMO been notified for release elsewhere in the Community by the same notifier?

Yes (x) No (.) If yes:

- Member State of notification FI, GB - Notification number FI: 22/M/17

EudraCT No. 2017-003194-33; 2017-001345-27; 2017-003859-36

Please use the following country codes: Austria AT; Belgium BE; Germany DE; Denmark DK; Spain ES; Finland FI; France FR; United Kingdom GB; Greece GR; Ireland IE; Iceland IS; Italy IT; Luxembourg LU; Netherlands NL; Norway NO; Portugal PT; Sweden SE

6. Has the same GMO been notified for release or placing on the market outside the Community by the same or other notifier?

Yes (x) No (.)


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If yes: - Member State of notification Outside the Community: USA, Canada & Australia - Notification number USA: IND 17148 and IND18301.

Canada: NSN 19738 Australia: DNIR 588

7. Summary of the potential environmental impact of the release of the GMOs.

In this Phase 1/2a clinical study Ad26.RSV.preF will be administered intramuscularly in RSV-seronegative toddlers aged 12 to 24 months. The clinical trial is taking place under conditions similar to contained use and during the administration of the vaccine no release into the environment occurs. Ad26.RSV.preF is a recombinant, replication-incompetent adenovirus vector and does not exist in nature. There is no data available on the potential impact of the release of Ad26.RSV.preF. Biodistribution and shedding however, are considered to be a feature of the replication incompetent adenovirus vector platform and the route of administration. Therefore, bio-distribution of Ad26.RSV.preF upon intramuscular (IM) injection is expected to be comparable to bio-distribution of other replication incompetent adenoviral vectors. A biodistribution study using Ad26.RSV.preF vaccine has not been performed. However, the biodistribution potential of the Ad26 vector has been evaluated in combination with another insert, using a Ad26-vectored HIV (Ad26.ENVA.01) in a study in New Zealand White (NZW) rabbits. In this study with Ad26.ENVA.01, the Ad26 vector showed a limited distribution profile, i.e., remaining primarily in the injection site muscle and distributing only to the draining lymph node and spleen. In addition, the Ad26 vector showed clearance within 3 months from most of the tissues. This limited biodistribution pattern and clearance is consistent regardless of type of adenovirus vector (Ad5 or Ad35), the construction, insert gene or method for preparation ([3]). As biodistribution is considered to be independent from the gene insert being expressed it can be assumed that Ad26.RSV.preF will distribute in the same way as the Ad26.ENVA.01 vaccine. Shedding data with Ad26 vector vaccines is available from IPCAVD001 and IPCAVD004 clinical study using Ad26.ENVA.01 at a dose of up to 1×1011 vp given IM ([4], [5]). Urine, throat and oropharyngeal samples were found negative for presence of infectious adenovirus. In a recent Phase 2 clinical study (VAC52150EBL2001) conducted in France, shedding of vector DNA was studied. In this study, an Ad26-vectored Ebola vaccine (Ad26.ZEBOV) was administered IM at a dose of 5×1010 vp. At all time points tested the level of Ad26.ZEBOV vector DNA in nasal and urine samples was below the lower limit of detection for all samples (data not published). Thus, these studies did not detect shedding of replication-competent adenovirus or vaccine vector DNA. Since the expressed transgene RSV preF does not change the biological properties of the replication-incompetent Ad26 vector it is expected that these results can be extrapolated to Ad26.RSV.preF. Therefore, the risk of shedding of Ad26.RSV.preF during the proposed study is considered negligible.


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The likelihood of Ad26.RSV.preF becoming persistent and invasive in natural habitats is minimal for the following reasons. Ad26.RSV.preF has been tested negative for RCA. The probability that the missing E1 function is complemented in humans is extremely low. In the theoretical situation that Ad26.RSV.preF re-acquired the ability to replicate reliably, the consequences would likely be minimal. Since the modified virus is replication incompetent, it is less pathogenic than the wild-type Ad26 and there is minimal capacity for colonization in natural ecosystems. If it is exposed to the environment, it is unlikely to survive for extended periods. Horizontal gene transfer is unlikely and due to Ad26.RSV.preF sequence characteristics there is no possibility to confer a selective advantage to bacteria or other microorganisms because it does not contain any prokaryotic promoters, any antibiotic or other types of resistance genes which would enhance or constrain their growth.

In regard to humans, the infection risk with Ad26.RSV.preF is negligibly since no release from the injected subjects is expected. In the case of transmission to unintended persons working with, coming into contact with, or in the vicinity of Ad26.RSV.preF administration the consequences for the individual are expected to be minimal.

Ad26.RSV.preF will be shipped in qualified, insulated shippers to clinical sites. The vaccines will be supplied in sealed single-dose vials, which will be stored in a secured location with no access for unauthorized personnel. Subjects of the trials will be vaccinated with Ad26.RSV.preF at the clinical sites under controlled conditions. Considerable care will be taken that personnel and the areas are not exposed to Ad26.RSV.preF. All wastes resulting from Ad26.RSV.preF handling are to be treated according to regular hospital procedure for infectious wastes. In case of accidental spillage, specific recommendation for decontamination and destruction are to be followed to avoid any risk of dispersion to the environment. Therefore, the only potential release is into the subject administered with Ad26.RSV.preF. Taking the above information into consideration, a biological dispersion of Ad26.RSV.preF to the environment is unlikely and its potential environmental impact is considered negligible.

B. Information relating to the recipient or parental organism from which the GMO is derived

1. Recipient or parental organism characterisation:

(a) Indicate whether the recipient or parental organism is a:

(select one only) viroid (.)


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RNA virus (.) DNA virus (x) bacterium (.) fungus (.) animal


(specify phylum, class) … other, specify … 2. Name

(i) order and/or higher taxon (for animals) Adenoviridae (ii) genus Mastadenovirus (iii) species Adenovirus Group D (iv) subspecies N/A (v) strain Type 26 (vi) pathovar (biotype, ecotype, race, etc.) N/A (vii) common name human adenovirus type 26 (Ad26)

Human adenovirus type 26, group D, has presumably been isolated from an anal specimen from a 9-month-old male, in Washington, DC, in 1956.

3. Geographical distribution of the organism (a) Indigenous to, or otherwise established in, the country where the notification is

made: Yes (.) No (.) Not known (x)

(b) Indigenous to, or otherwise established in, other EC countries: (i) Yes (x)

If yes, indicate the type of ecosystem in which it is found: Atlantic .. Mediteranean .. Boreal .. Alpine .. Continental .. Macaronesian ..

(ii) No (.) (iii) Not known (.)

Adenovirus type 26 wild type is a human D group adenovirus which rarely causes disease in humans. Group D adenoviruses are considered less pathogenic than e.g., B or C group


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adenoviruses, as they rarely cause disease in immunocompetent hosts other than conjunctivitis. Adenovirus is prevalent worldwide, and is ubiquitous throughout the year, especially during late winter and early spring. Low to moderate titers of baseline Ad26-specific neutralizing antibodies were observed in sub-Saharan Africa, Thailand, and Brazil, amongst other regions. [6, 7]Ad26 is a rare human pathogen and the host is human beings, independent of the ecosystem. It can be assumed that Ad26 wildtype also circulates in humans in Spain, however at a low prevalence.

(c) Is it frequently used in the country where the notification is made? Yes (.) No (.) not known (x) In Spain, the country of notification, a low seroprevalence of Ad26 virus in humans is expected, comparable to Belgium ([8]).

(d) Is it frequently kept in the country where the notification is made?

Yes (.) No (x) 4. Natural habitat of the organism

(a) If the organism is a microorganism

water (.) soil, free-living (.) soil in association with plant-root systems (.) in association with plant leaf/stem systems (.) other, specify humans

(b) If the organism is an animal: natural habitat or usual agroecosystem:

N/A 5. (a) Detection techniques Detection of wild type replication competent Ad26 adenoviruses, can be performed by

adenoviral cultures in MRC5 and A549 cells and detection using an anti-hexon antibody that showed reactivity against the Ad26 adenovirus hexon protein. Alternatively, Ad26 viruses can be detected with PCR using adenovirus general or Ad26 virus specific sequences

(b) Identification techniques

Wild type Ad26 viruses are identified using PCR with sequences specific for Ad26 virus DNA sequencing can also be used for the identification of adenoviruses.

6. Is the recipient organism classified under existing Community rules relating to the protection of human health and/or the environment?

Yes (x) No (.) If yes, specify


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Human adenovirus is classified as a group 2 biological agent as per the European Economic Community classification for the protection of workers with biological agents (Directive 2000/54/EC). The group 2 designation applies to agents that can cause human disease and might be a hazard to workers, that are unlikely to spread to the community and for which there is usually effective prophylaxis or treatment available. Based on the mild disease of human adenovirus 26 in healthy humans and results of toxicity studies that demonstrated safety and tolerability, the GMO is not considered to pose a risk to human health. Manipulation and production in the cell line PER.C6 was performed at BSL-2.

7. Is the recipient organism significantly pathogenic or harmful in any other way (including its extracellular products), either living or dead? Yes (.) No (x) Not known (.)

If yes:

(a) to which of the following organisms:

humans (.) animals (.) plants (.) other (.)

(b) give the relevant information specified under Annex III A, point II. (A)(11)(d) of

Directive 2001/18/EC

Adenoviruses are classified as Group 2 under Directive 2000/54/EC due to their limited pathogenicity. Adenovirus type 26 wild type is a human D group adenovirus which rarely causes disease in humans. Group D adenoviruses are considered less pathogenic than e.g., B or C group adenoviruses, as they rarely cause disease in immunocompetent hosts other than conjunctivitis. Group D adenoviruses are most commonly associated with diarrhoea in AIDS patients. Normally, the virus enters the respiratory tract or the eyes through aerosols produced by infected individuals. In general, wild type Adenovirus type 26 typically can cause gastrointestinal infections, moderate conjunctivitis and very mild rhinitis, but is only very rarely described as a human pathogen in natural infections. Most infections are minor in nature and self-limiting. Adenoviruses are usually not integrated into the host cells genome and do not persist in lymphoid tissues. Adenovirus may be transmitted between individuals via fecal-oral route, respiratory droplets, hand-to-eye and venereal transfer. Adenoviruses can transduce mammal cells but no other cells. Ad26 infection is limited to humans.


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8. Information concerning reproduction

(a) Generation time in natural ecosystems: The adenoviral life cycle starts with binding of the viral fiber knob to cell surface receptors. After other specific binding and recognition events including the viral penton protein and the host’s integrins, the virus is taken up into the cell by endocytosis. The virus particle escapes from the endosome and the viral DNA is released into the host cell nucleus. There, early genes and late genes are transcribed. Early gene products are regulatory proteins that enable efficient viral DNA replication, activate other viral proteins and ensure escape from the host’s immune response. After DNA replication, late genes are transcribed that code for structural proteins. These proteins together with replicated DNA molecules form new viral particles that leave the cell by cell lysis. Wild type adenovirus replication is an efficient process and progeny virus can be produced in less than 2 days.

(b) Generation time in the ecosystem where the release will take place: See Section 8 (a)

(c) Way of reproduction: Sexual .. Asexual x

(d) Factors affecting reproduction: The outcome of an adenovirus infection depends on the animal species and cell type involved. Adenovirus Type 26 is restricted to humans.

9. Survivability

(a) Ability to form structures enhancing survival or dormancy:

(i) endospores (.) (ii) cysts (.) (iii) sclerotia (.) (iv) asexual spores (fungi) (.) (v) sexual spores (fungi) (.) (vi) eggs (.) (vii) pupae (.) (viii) larvae (.) (ix) other, specify

Adenovirus do not form structures enhancing survival or dormancy

(b) Relevant factors affecting survivability: Wild type Ad26 virus is able to persist in aerosols and water. Stability decreases significantly as temperature is increased. Under normal environmental conditions, Ad26 is expected to lose viability within days to weeks. Adenoviruses are resistant to lipid disinfectants but are inactivated by formaldehyde and chlorine. They can be inactivated by contact with 1:5 dilution of bleach for 1 minute [9].


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10. (a) Ways of dissemination Adenoviruses, in general, are spread via direct contact, aerosols, water droplet, through sneezing/coughing by infected individuals and possible spread through fecal-oral route.

(b) Factors affecting dissemination

Factors affecting adenovirus dissemination, in general, are exposure dose, formation of aerosols, and closeness of contacts.

11. Previous genetic modifications of the recipient or parental organism already notified for

release in the country where the notification is made (give notification numbers) NA C. Information relating to the genetic modification 1. Type of the genetic modification

(i) insertion of genetic material (x) (ii) deletion of genetic material (x) (iii) base substitution (.) (iv) cell fusion (.) (v) others, specify …

2. Intended outcome of the genetic modification

• Adenovirus type 26 (Ad26) was rendered replication incompetent by deletion of Early region 1 and partial deletion of Early region 3 (ΔE1/ ΔE3).

• Ad26 E4 open reading frame (orf) 6 and part of E4orf6/7 were exchanged for those of adenovirus type 5 (Ad5) to allow production of replication incompetent Ad26 vectors in Ad5 E1 complementing cell lines i.e., PER.C6®.

• A transgene expression cassette is placed in the E1 deletion using a human cytomegalovirus immediate early promoter (CMV) and a simian virus 40 (SV40) derived polyadenylation signal for strong ubiquitous expression of a transgene.

• The synthetic sequence for the RSV preF gene was introduced in the transgene expression cassette of the replication-incompetent adenovirus type 26 vectors [Δ Early region 1/Early region 3 (E1/E3)]

3. (a) Has a vector been used in the process of modification?

Yes (x) No (.) If no, go straight to question 5. (b) If yes, is the vector wholly or partially present in the modified organism?

Yes (x) No ()


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If no, go straight to question 5. 4. If the answer to 3(b) is yes, supply the following information (a) Type of vector plasmid (x) pAdapt26 plasmid harboring the RSV transgene bacteriophage (.) virus (.) cosmid (x) Ad26 cosmid

transposable element (.) other, specify … (b) Identity of the vector

• A plasmid and a cosmid vector were used in the process of modification. The left part of the linear double-stranded Adenovirus 26 genome was cloned into a plasmid vector called pAdapt. The larger right part of the Adenovirus 26 genome was cloned into a cosmid vector, also called Ad backbone. The modifications listed under C.2, Intended outcome of the genetic modification, were made in the plasmid and cosmid, respectively.

• pAdapt26 harboring the RSV.preF transgene expression cassette and Ad26 cosmid were linearized and co-transfected into the production cell line PER.C6. Homologous recombination results in formation of the replication-incompetent Ad26.RSV.preF. The plasmid and cosmid are constructed in a way that only the desired Adenovirus vector and transgene sequences are present in the Ad26.RSV.preF vector. No bacterial plasmid or cosmid sequence or bacterial resistance genes are present in Ad26.RSV.preF vector sequence.

- Figure:1 Generation of E1/E3 Deleted Recombinant Ad26 Vectors on PER.C6® Using the

pAdapt® Vector System. • TG = RSV.preF, ITR = Inverted terminal repeat, E1, E2B, E2A, E3, E4 = Adenovirus early genes, L1-L5 = Adenovirus late genes, Ad5orf6 = Ad5 E4 orf6, supports replication of rAd26 on Ad5- E1 complementing cell lines.


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(c) Host range of the vector E. coli laboratory strains (d) Presence in the vector of sequences giving a selectable or identifiable phenotype

Yes (x) No () antibiotic resistance (x) other, specify … Indication of which antibiotic resistance gene is inserted pAdapt26: Ampicillin resistance gene

Ad26 cosmid: Kanamycin and Ampicillin resistance genes Note that the antibiotic resistance genes are only part of the plasmid and cosmid backbone. Upon recombination in PER.C6 and generation of the final vaccine vector Ad26.RSV.preF, no antibiotic resistance gene is present.

(e) Constituent fragments of the vector

• pAdapt26.RSV.preF contains the left part of the genome ranging from the left ITR to nucleotide 5913 comprising pIX and IV a2.

• The Ad26 cosmid contains the overlap region comprising pIX and IV a2 and the remaining right end sections of the Ad26 genome where the Ad26 E3 gene has been partially deleted and the Ad26 E4 open reading frame (orf) 6 and part of E4orf6/7 has been exchanged for those of Adenovirus type 5 (Ad5).

(f) Method for introducing the vector into the recipient organism

(i) transformation (.) (ii) electroporation (.) (iii) macroinjection (.) (iv) microinjection (.) (v) infection (.) (vi) other, specify (x) co-transfection of linearized

pAdapt26.RSV.preF and Ad26 cosmid 5. If the answer to question B.3(a) and (b) is no, what was the method used in the process of modification?

(i) transformation (.) (ii) microinjection (.) (iii) microencapsulation (.) (iv) macroinjection (.) (v) other, specify …


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6. Composition of the insert (a) Composition of the insert Ad26.RSV.preF harbours a transgene expression cassette in place of the E1 deletion at the

left end of the Ad26 vector genome. The transgene expression cassette consists of a human cytomegalovirus immediate early promoter and a simian virus 40 derived polyadenylation signal and encodes a synthetic RSV F sequence. The synthetic sequence encodes a pre-fusion conformation-stabilized F protein (preF) derived from the RSV A2 strain. The synthetic sequence for the transgene RSV.preF was cloned into the pAdapt26 adapter plasmid by standard molecular cloning techniques. The RSV.preF transgene encodes an RSV structural protein. No effects on the vector sequences due to the insertion of the transgenes into the vector were found. No additional open reading frames were created.

(b) Source of each constituent part of the insert The synthetic sequence encodes a pre-fusion conformation-stabilized F protein (preF)

derived from the RSV A2 strain. Expression of the preF transgene is controlled by a strong ubiquitous promoter derived from human cytomegalovirus (hCMV). The polyadenylation signal is derived from simian virus 40 (SV40). The promoter and polyadenylation signal are commonly used genetic control elements.

(c) Intended function of each constituent part of the insert in the GMO A synthetic transgene, encoding the Respiratory Syncytial Virus (RSV) F protein stabilized in the prefusion confirmation (preF) is inserted into the adenoviral vector genome. This transgene is expressed in the vaccinated individual and elicits the vaccinee’s immune response against RSV. The E1 region of Ad26 is replaced by a transgene expression cassette, in which the RSV preF is placed under control of a human CMV promoter and followed by a SV40 polyadenylation signal to ensure expression of the transgenes upon intramuscular (IM) administration of a vaccinee.

(d) Location of the insert in the host organism

- on a free plasmid (.) - integrated in the chromosome (.)

- other, specify Integrated in the double-stranded DNA genome in the adenovirus ds DNA replacing the E1 region. No integration of the insert into the genome of vaccinated individuals.

(e) Does the insert contain parts whose product or function are not known?

Yes (.) No (x) If yes, specify …

D. Information on the organism(s) from which the insert is derived 1. Indicate whether it is a:

viroid (.)


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RNA virus (x) DNA virus (.) bacterium (.) fungus (.) animal


(specify phylum, class) … other, specify … 2. Complete name

(i) order and/or higher taxon (for animals) Mononegavirales (ii) family name for plants Paramyxoviridae (iii) genus Orthopneumovirus (iv) species human Respiratory Syncytial Virus (v) subspecies … (vi) strain RSV A2 strain (vii) cultivar/breeding line … (viii) pathovar … (ix) common name Respiratory Syncytial Virus

3. Is the organism significantly pathogenic or harmful in any other way (including its extracellular products), either living or dead?

Yes (x) No (.) Not known (.) If yes, specify the following:

(a) to which of the following organisms:

humans (x) animals (.) plants (.) other ..

(b) are the donated sequences involved in any way to the pathogenic or harmful

properties of the organism Yes () No (x) Not known (.) If yes, give the relevant information under Annex III A, point II(A)(11)(d):

In the context of wild type RSV, the RSV fusion protein gene encodes a structural virus protein. The wildtype RSV F protein is a class I viral fusion protein which can mediate membrane fusion between the viral membrane and the cell membrane, or when expressed by host cells also between neighboring cell membranes. The

https://en.wikipedia.org/wiki/Orthopneumovirus


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RSV F protein was selected as a transgene because it is highly conserved and forms an important target of neutralizing antibodies. The encoded transgene RSV preF is a synthetic sequence and its gene product is stabilized in the pre-fusion conformation. The preF protein is not part of the Ad26.RSV.preF capsid and thus, does not have an influence on the transduction capacity of Ad26, and does not change the host spectrum, cell tropism or environmental stability of the Ad26 vector.

4. Is the donor organism classified under existing Community rules relating to the protection of human health and the environment, such as Directive 90/679/EEC on the protection of workers from risks to exposure to biological agents at work?

Yes (x) No (.) If yes, specify …

Relating to the protection of human health and the environment, Respiratory Syncytial Virus is classified as a group 2 biological agent as by the existing Community rules such as Directive 90/679/EEC on the protection of workers from risks to exposure to biological agents at work.

5. Do the donor and recipient organism exchange genetic material naturally? Yes (.) No (x) Not known (.) E. Information relating to the genetically modified organism 1. Genetic traits and phenotypic characteristics of the recipient or parental organism which have been changed as a result of the genetic modification (a) Is the GMO different from the recipient as far as survivability is concerned?

Yes () No (x) Not known (.) Specify …

Survivability or stability of the GMO Ad26.RSV.preF should be similar to the wild type Ad26 virus. Ad26.RSV.preF is however replication-incompetent.

(b) Is the GMO in any way different from the recipient as far as mode and/or rate of

reproduction is concerned? Yes (x) No (.) Unknown (.)

Specify … Ad26.RSV.preF is replication-incompetent and harbors the RSV preF transgene. (c) Is the GMO in any way different from the recipient as far as dissemination is

concerned? Yes (x) No (.) Not known (.)

Specify … Wild type adenovirus replication is an efficient process and progeny virus can be produced in less than 2 days, whereas Ad26.RSV.preF cannot replicate in cells


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which do not express the adenoviral E1 region and dissemination is limited, unlike the wild type virus would be present. Dissemination is restricted to the subjects receiving the GMO in the clinical study.

(d) Is the GMO in any way different from the recipient as far as pathogenicity is

concerned? Yes (x) No (.) Not known (.)

Specify … Ad26.RSV.preF cannot replicate in cells which do not express the adenoviral E1

region and is therefore not considered to be pathogenic. 2. Genetic stability of the genetically modified organism

Ad26.RSV.preF is considered genetically stable. Genetic stability is tested during different steps of the production process. Plaque purified Ad26.RSV.preF vector was used to produce virus seed lots. Virus seed lots are extensively tested and characterised which includes sequence analysis (compared to theoretical sequence). Virus seed lots containing the correct sequence serve as starting material for the production of each virus lot. Virus lots are subjected to sequence analysis. During manufacturing the GMO identity is confirmed to ensure that the vector with correct type and insert is present in the drug product. The Adenovirus vector identity test is according to Ph. Eur. 5.14, EMA/CHMP/VWP/141697/2009, and ICH Q6B.

3. Is the GMO significantly pathogenic or harmful in any way (including its extracellular products), either living or dead?

Yes (.) No (x) Unknown (.) (a) to which of the following organisms? humans (.) animals (.) plants (.) other …

(b) give the relevant information specified under Annex III A, point II(A)(11)(d) and II(C)(2)(i) –

The Ad26.RSV.preF vaccine is currently being evaluated in the (ongoing) studies: -In older adult participants (≥60 years) in stable health: VAC18193RSV1003,

VAC18193RSV1004 and VAC18193RSV2003 - In healthy adults (≥18 to ≤50 years): VAC18193RSV2002 -In healthy adults (≥18 to ≤50 years) and healthy RSV-seropositive toddlers (≥12 to ≤24 months): VAC18194RSV2001. Up to today, no safety concerns were revealed; Two initial Phase 1 clinical studies evaluating the safety, tolerability and immunogenicity of the prototype vaccine Ad26.RSV.FA2 (expressing the wild-type RSV F protein from the RSV A2 strain,


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not stabilized in the prefusion conformation, and thus differing by only 5 amino-acids from the RSV preF sequence expressed by Ad26.RSV.preF) in healthy adults aged 18 to 50 years have been completed (VAC18192RSV1001 and VAC18192RSV1003 in 48 and 32 subjects, respectively, of which 35 and 24 subjects, respectively, received Ad26.RSV.FA2 at a dose of 5×1010 vp). Both studies indicate that there have been no safety concerns following vaccination in either study. Other Ad26-vectored vaccines have been evaluated in adults, including vaccines against human immunodeficiency virus (HIV) (Ad26.ENVA.012,3), malaria (Ad26.CS.018,28), and Ebola virus (Ad26.ZEBOV23).). All Ad26-based vaccines were found to be well tolerated. Several other studies are currently ongoing, and no safety concerns have been raised to date.

Extensive non-clinical studies have been performed with the Ad26.RSV.preF

vaccine candidate, including immunogenicity, efficacy, and toxicity studies in preparation for conducting clinical trials. Regarding the toxicology study, a 57-day intermittent dose toxicity study was conducted in rabbits includingAd26.RSV.preF. Intermittent IM administration of Ad26.RSV.preF at 1×1011 vp on 5 consecutive occasions was well tolerated.

Although no shedding data of Ad26.RSV.preF is available, other shedding studies

have been published including a shedding study using Ad26 adenovirus vectored expressing a HIV antigen and did not detect shedding of replication-competent adenovirus or vaccine vector DNA.

Wildtype Ad26 virus is a group D human adenovirus which rarely causes disease in humans. Compared to the parental organism, the Ad26.RSV.preF lacks regions essential for viral growth. Ad26.RSV.preF is thereby disabled and incapable of establishing a productive, transmissible infection in humans, and is therefore considered not to be pathogenic. Since Ad26.RSV.preF is replication incompetent, there is minimal capacity for colonization in natural ecosystems. Due to replication incapacity of the Ad26.RSV.preF, no interaction of the Ad26.RSV.preF with the prey, hosts, symbionts, predators, parasites and pathogens is expected. Potential recombinants resulting from recombination with wildtype adenoviruses would not pose a higher risk level than a wildtype infection that is already present and these recombinants would not be able to disseminate in the human body or to the environment. The unlikely event of trans-complementation of the E1 missing function by other viruses (e.g. HPV, EBV) cannot be excluded, but would be limited to transduced co-infected cells only, as Ad26.RSV.preF remain replication incompetent. Therefore, dissemination of the vector will not take place. Furthermore, the absence of any sequence homology between the vector and the PER.C6® manufacturing process prevents the formation of RCA. All produced A26 batches at Janssen Vaccines & Prevention B.V., including this GMO, have been tested negative for a control test for the detection of RCA.


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The GMO does not contain any prokaryotic promotors, any antibiotics or other types of resistance genes, thereby excluding horizontal gene transfer. Dissemination is restricted to the subjects receiving the GMO in the clinical study; infection of healthcare workers. Adenovirus vectors are known to be present as episomal structures in the transduced cells, and do not likely present a risk of integration in the host genome. Many other adenoviral vectors have been constructed by deletion of E1 region which encodes key genes required for viral growth. These E1 deleted adenoviral vectors are disabled and incapable of establishing a productive, transmissible infection in humans. Therefore, these E1 deleted vectors can be considered to be non-pathogenic in humans and may be handled safely at Containment Level 1 in absence of replication-incompetent adenovirus ([10]).

4. Description of identification and detection methods (a) Techniques used to detect the GMO in the environment Virus identity testing is performed to confirm the Adenoviral subtype of the vector and

transgene by polymerase chain reaction (PCR). First, the viral DNA is extracted and purified. Purified DNA from the test sample is used for PCR with primers that have been designed to specifically amplify the transgene, as well as the adenovirus specific regions. Upon amplification, the size of the PCR product obtained with the test article is compared to a control amplification performed in parallel on purified plasmid DNA. Concordance between the size of the test article and the control is indicative of the virus identity. In addition, identity is confirmed by sequencing the transgene and its flanking regions

(b) Techniques used to identify the GMO See under 4 (a) F. Information relating to the release 1. Purpose of the release (including any significant potential environmental benefits that may be expected)

Janssen Vaccines & Prevention B.V. is developing a prophylactic RSV vaccine for children from 2 months of age. Ad26.RSV.preF will be administered by intramuscular injection (IM) to subjects participating in this international, multicenter, randomized, placebo-controlled, observer-blind Phase 1/2a clinical study (VAC18194RSV2002) to evaluate the safety, tolerability and immunogenicity of Ad26.RSV.preF at 2×1010 vp in seronegative toddlers aged 12 to 24 months. The purpose of this trial is to evaluate the safety, reactogenicity and immunogenicity of this RSV vaccine candidate when administered with IM immunization using a 0, 4 and 8 week schedule. In this international study the GMO will be administered to 48 subjects, and 48 subjects will receive placebo. It is anticipated that a maximum of 20 subjects will be recruited in Spain during this multi-center study.


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Duration of this study is anticipated to be 30 months, including follow up of 2 years. There is no deliberate release of Ad26.RSV.preF into the environment at large and there is no expected significant benefit for the environment.

2. Is the site of the release different from the natural habitat or from the ecosystem in which the recipient or parental organism is regularly used, kept or found?

Yes (.) No (x) If yes, specify … Not applicable, the GMO is not found in a natural habitat besides, to a limited percentage,

in the human population. 3. Information concerning the release and the surrounding area (a) Geographical location (administrative region and where appropriate grid

reference): The clinical trial will be conducted at the following clinical sites:

• HOSPITAL. UNIVERSITARIO. 12 DE OCTUBRE Avenida. de Córdoba, s/n, 28041 MADRID (Spain)

• Hospital General Universitario Gregorio Marañón

Calle del Dr. Esquerdo, 46, 28007 Madrid, Spain

• HOSPITAL. UNIVERSITARIO. LA PAZ Paseo de la Castellana, 261, 28046 Madrid

• HOSPITAL. CLINICO UNIVERSITARIO. DE SANTIAGO

Rúa da Choupana, s/n, 15706 Santiago de Compostela, A Coruña Ad26.RSV.preF will be administered under controlled conditions at the clinical sites.

(b) Size of the site (m2): … m2 (i) actual release site (m2): … m2

(ii) wider release site (m2): … m2 No specific size; immunizations are going to be performed in hospital rooms

(c) Proximity to internationally recognised biotopes or protected areas (including

drinking water reservoirs), which could be affected: No environmental sites outside the hospital rooms are anticipated to become affected. Containment measures during the administration of Ad26.RSV.preF to subjects will exclude the release of Ad26.RSV.preF into the environment. Personal protective equipment will be used to avoid exposure to Ad26.RSV.preF to the medical personnel involved in the administration of the product.


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Therefore, it is negligible that Ad26.RSV.preF will be released to the proximity of significant biotopes, protected areas or drinking water supplies as possible potential sites, which could be affected.

(d) Flora and fauna including crops, livestock and migratory species which may

potentially interact with the GMO There is a negligible likelihood of such exposure. See 3 (e)

4. Method and amount of release

(a) Quantities of GMOs to be released: In the notified country, Spain, it is anticipated that a maximum of 20 subjects will

be recruited; Ad26.RSV.preF will be administered to approximately 10 subjects (RSV seronegative toddlers from 12-24 months) who will receive 3 doses of 2.5×1010 vp four weeks apart. In total, it is estimated that 30 vials of Ad26.RSV.preF will be administered during this trial in Spain.

(b) Duration of the operation:

Immunization of the subjects via IM will take a few minutes. The total study will last for approximately 30 months.

(c) Methods and procedures to avoid and/or minimize the spread of the GMOs beyond

the site of the release At the clinical sites, considerable care will be taken to ensure that Ad26.RSV.preF is contained and that personnel and the areas are not exposed. All wastes resulting from handling of Ad26.RSV.preF are to be treated according to regular hospital procedure for infectious wastes. In case of accidental spillage, specific recommendation for decontamination and destruction are to be followed to avoid any risk of dispersion to the environment.

5. Short description of average environmental conditions (weather, temperature, etc.)

Not applicable: given that Ad26.RSV.preF is prepared for administration and given to subjects in hospital clinical environment, it is not anticipated that Ad26.RSV.preF will be released into the environment.

6. Relevant data regarding previous releases carried out with the same GMO, if any, specially related to the potential environmental and human health impacts from the release.

The Ad26.RSV.preF vaccine is currently being evaluated in the following studies: VAC18193RSV1003 is a single-center, randomized, placebo-controlled, double-blind, FIH Phase

1 study to evaluate the safety, tolerability and immunogenicity of 2 Ad26.RSV.preF vaccinations, administered 1 year apart, in 72 male and female participants aged 60 years and older in stable health in the USA (ClinicalTrials.gov Identifier: NCT02926430). Safety and immunogenicity data from the unblinded interim analysis 28 days post-Dose 1 from all 72 subjects who received Ad26.RSV.preF (5×1010 vp or 1×1011 vp) or placebo


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confirmed the immunogenicity of the vaccine. No safety concerns were revealed; the reactogenicity of both doses was comparable.

VAC18193RSV1004 is an ongoing multi-center, randomized, placebo-controlled, double-blind Phase 1/2a study to evaluate the safety and immunogenicity of Ad26.RSV.preF and/or RSV preF protein combinations in healthy male and female participants aged 60 years and older.

VAC18193RSV2002 is an ongoing single-center, randomized, placebo-controlled, double-blind Phase 2a exploratory human challenge study, to evaluate the prophylactic efficacy of a single immunization of Ad26.RSV.preF against RSV infection in a virus challenge model in healthy male and female participants aged 18-50 years.

VAC18193RSV2003 is an ongoing single-center, randomized, placebo-controlled, double-blind Phase 2a study, to evaluate the safety and immunogenicity of seasonal influenza vaccine and Ad26.RSV.preF, with and without co-administration in 180 adult male and female participants aged ≥60 years of age in stable health. The study is fully enrolled, and participants have received both doses of study vaccine

VAC18194RSV2001 is an ongoing multi-center, randomized, double-blind, placebo-controlled Phase 1/2a study, to evaluate the safety, tolerability and immunogenicity of Ad26.RSV.preF in 12 male and female adults aged ≥18 to ≤50 years and 48 male and female RSV-Seropositive toddlers aged ≥12 to ≤24 months. Enrollment and dosing of study participants is ongoing

No shedding data is available for Ad26.RSV.preF. Shedding data with other Ad26 vector vaccines is available. Study IPCAVD001 enrolled 30 participants in a dose-escalation Phase 1 study, who received IM doses of up to 1×1011 vp Ad26.ENVA.01 ([5]). Urine, throat, and oropharyngeal samples were analyzed at different time points of the study. The rationale for sampling was development of an upper respiratory infection in vaccinated participants as a sign of possible adenoviral illness. Adenovirus cultures were performed to detect infectious adenovirus, and all samples were negative for adenovirus. Thus, no adenovirus shedding in any clinical sample was found upon intramuscular administration of an Ad26 vector. Shedding has also been assessed in a subset of participants from the IPCAVD004 study ([4]). This clinical study assessed the safety and immunogenicity of IM doses of Ad26.ENVA.01 (5×1010 vp), and Ad35-ENV (5×1010 vp). Shedding was analyzed by adenovirus cultures of urine and respiratory secretions 14 days after vaccination and during intercurrent illnesses; all shedding samples were negative for adenovirus irrespective of the Ad vector (Ad26 or Ad35) administered. The IPCAVD001 and IPCAVD004 studies tested for excretion of replicating adenovirus but shedding of replication incompetent vector particles was not assessed. This has been evaluated in a recent Phase 2 clinical study (VAC52150EBL2001) in France. In this study, an Ad26-vectored Ebola vaccine (Ad26.ZEBOV) was administered IM at a dose of 5×1010 vp. Presence of Ad26.ZEBOV vector DNA in nasal and urine samples was tested by a quantitative PCR-based assay which would detect replication competent and incompetent Ad26.ZEBOV. At all time points tested, the level of Ad26.ZEBOV vector DNA was below the lower limit of detection for all tested samples (data not published). These findings are consistent with shedding studies of adenoviral vectors derived from other human or non-human adenoviral types which did not detect shedding of replication-competent adenovirus vectors ([11]).


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G. Interactions of the GMO with the environment and potential impact on the

environment, if significantly different from the recipient or parent organism 1. Name of target organism (if applicable)

(i) order and/or higher taxon (for animals) … (ii) family name for plants … (iii) genus homo (iv) species sapiens (v) subspecies … (vi) strain … (vii) cultivar/breeding line … (viii) pathovar … (ix) common name human

2. Anticipated mechanism and result of interaction between the released GMOs and the target organism (if applicable)

Ad26.RSV.preF will induce an immune response (humoral and cellular responses) in the vaccinated individuals but will not modify the characteristics of the human recipients. The induced immune response will eliminate the transduced cells and thereby also the presence of Ad26.RSV.preF in the human being.

3. Any other potentially significant interactions with other organisms in the environment

Ad26.RSV.preF will be administered in a hospital setting, therefore it is highly unlikely that the GMO will come in contact with animal species. Ad26.RSV.preF is replication incompetent and it is highly unlikely that the it will be transferred to the environment or to other organisms. As Ad26.RSV.preF cannot replicate there is no basis that the inserted genetic trait (RSV preF) could be transferred to the environment at large.

4. Is post-release selection such as increased competitiveness, increased invasiveness for the GMO likely to occur? Yes (.) No (x) Not known (.) Give details As Ad26.RSV.preF cannot replicate, there appears to be no chance that the inserted genetic

trait will induce increased competitiveness, or increased invasiveness.

A theoretically event is that Ad26.RSV.preF transduces a cell which has been infected with an adenovirus, to form a new GMO which is recombination competent, which might spread further in the environment. For this scenario to happen, homologous sequences between an Ad26.RSV.preF vector and other wildtype adenoviruses are required. Adenoviral vector DNA of Ad26 vectors are found at the site of administration in the muscle, the draining lymph nodes and in the spleen, while common wildtype adenovirus DNA is found in mucosal lymphoid tissue. As vector DNA and wildtype adenovirus DNA do not locate to


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the same body compartments, this precludes recombination events. In addition, only low quantities of vector DNA and of persisting wildtype adenoviruses are found in tissues, which highly reduces any chance of recombination. Furthermore, in the theoretical event of recombination, the resulting virus would be less fit than the infecting wildtype virus and therefore not be able to disseminate. In summary, recombination events are possible but not likely. The resulting recombinants would however not pose a higher risk level than a wildtype infection that is already present and the recombinants would not be able to disseminate in the human body or to the environment. Another theoretical event is the release into the environment by trans-complementation of E1 deleted functions by alternative viral proteins from other viruses. It is described in literature that replication-incompetent Ad5 vectors can be trans-complemented by alternative viral proteins from other viruses such as Epstein Barr virus (EBV) or human papillomavirus (HPV). While EBV is mainly found in B cells and epithelial cells, HPV infections are restricted to mucosal surfaces in the genital tract and in the oropharynx. In the theoretical event that Ad26.RSV.preF vaccine vectors is present at the site of EBV or HPV infection, only a lytic EBV or HPV infection could theoretically lead to replication of the vaccine vector limited to the EBV or HPV infected cells. Produced Ad26.RSV.preF could potentially transduce neighboring cells. No further dissemination will take place as Ad26.RSV.preF produced particles remain replication incompetent in all other cells. This supports the risk for release into the environment by trans-complementation as negligible.

5. Types of ecosystems to which the GMO could be disseminated from the site of release and in which it could become established

Ad26.RSV.preF will be administered to subjects in a hospital room. Considerable care will be taken to ensure that Ad26.RSV.preF is contained and that personnel and the areas are not exposed to it. Dissemination would be limited to humans in close contact with the subject during the administration (healthcare workers administering Ad26.RSV.preF or any other person in close contact with the subjects) and the surrounding areas. In the very unlikely event that Ad26 vectors are released into the environment, they are not able to generate infectious progeny.

6. Complete name of non-target organisms which (taking into account the nature of the receiving environment) may be unintentionally significantly harmed by the release of the GMO

(i) order and/or higher taxon (for animals) … (ii) family name for plants … (iii) genus … (iv) species … (v) subspecies …


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(vi) strain … (vii) cultivar/breeding line … (viii) pathovar … (ix) common name …

Not applicable.

7. Likelihood of genetic exchange in vivo (a) from the GMO to other organisms in the release ecosystem: Highly unlikely, see section G3 (b) from other organisms to the GMO: Highly unlikely, see section G3

(c) likely consequences of gene transfer: Highly unlikely, adenoviruses are considered non-integrating viruses because of the inability of the virus to integrate into the host chromosomes

8. Give references to relevant results (if available) from studies of the behaviour and characteristics of the GMO and its ecological impact carried out in stimulated natural environments (e.g. microcosms, etc.): Not available 9. Possible environmentally significant interactions with biogeochemical processes (if different from the recipient or parental organism) Not applicable H. Information relating to monitoring 1. Methods for monitoring the GMOs

The intended function of Ad26.RSV.preF is to induce RSV preF specific RSV immune responses, which will be measured by assessment of the humoral and cellular responses against RSV preF. In addition, subjects participating in the clinical trial using Ad26.RSV.preF will be monitored for clinical assessment (e.g. physical examinations), and adverse event monitoring.

2. Methods for monitoring ecosystem effects Ecosystems effects will not be monitored as Ad26.RSV.preF is not naturally present in any

ecosystem. 3. Methods for detecting transfer of the donated genetic material from the GMO to other organisms It is highly unlikely that transfer of donor genetic material from Ad26.RSV.preF will be

transferred to other organisms (see G7c).


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4. Size of the monitoring area (m2) … m2 Not applicable 5. Duration of the monitoring Not applicable 6. Frequency of the monitoring Not applicable I. Information on post-release and waste treatment 1. Post-release treatment of the site The injection site will be covered with a plaster of bandage. The rooms in the medical

facility used to prepare and administer the vaccine will be cleaned before and after manipulation with a standard disinfectant active on Adenoviruses. Surfaces shall be decontaminated and cleaned after use with an appropriate disinfectant. Validated methods for cleaning surfaces include exposure with 0.1 M NaOH for at least 15 min.

2. Post-release treatment of the GMOs Materials in contact with Ad26.RSV.preF should be considered as contaminated and all

wastes (including vaccine vials, needles and syringes) should be placed in biohazard bins directly following administration of the IMP.

Used study materials will be destroyed by the clinical site following institutional

procedures for the disposal of biohazard material. 3. (a) Type and amount of waste generated

Based on the assumption that 10 subjects will be recruited that will receive Ad26.RSV.preF in the notified country, a total of 30 vials are planned to be used. The Ad26.RSV.preF is supplied in a glass vial, stoppered, and capped with seals. The general biohazard waste is estimated to be 30 glass vials, stoppers, caps and anticipated needles syringes, gloves and packaging.

3. (b) Treatment of waste All equipment, supplies including gloves, and receptacles in contact with Ad26.RSV.preF

shall be directly handled and disposed of in a biohazard container. Sharps (used ampules, needles, syringes and vials containing Ad26.RSV.preF) shall be disposed of in biohazard sharps containers.

J. Information on emergency response plans 1. Methods and procedures for controlling the dissemination of the GMO(s) in case of unexpected spread


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Ad26.RSV.preF is an IMP intended for use in a controlled clinical trial to be conducted at qualified medical facilities and under controlled conditions and handling procedures. In case of accidental spillage, specific recommendation for decontamination and destruction are to be followed to avoid any risk of dispersion to the environment, capturing all remaining liquid into spill absorbent material and place them in leak-proof container suitable for disposal in accordance with applicable waste disposal regulations. The GMO is susceptible to decontamination by e.g., 0.25M NaOH or 1% Virkon.

In case of skin contact . Disinfect skin and wash off with plenty of water and soap. Consult a physician. In case of eye contact. Flush eyes immediately 10-15 minutes under running water. Remove contact lenses. Consult a physician.

2. Methods for removal of the GMO(s) of the areas potentially affected

See section J.1.

3. Methods for disposal or sanitation of plants, animals, soils, etc. that could be exposed during or after the spread Not applicable 4. Plans for protecting human health and the environment in the event of an undesirable effect

Subjects included in the clinical trial will be monitored for the occurrence of adverse events and serious adverse events (SAE) according to the clinical protocol. Each SAE will be recorded and assessed by the hospital staff and the study sponsor, and Health Authorities will be notified when applicable. Adverse events will be registered and reported according to detailed procedures in the clinical study protocol. In case of an undesirable effect, this medicine will be put on hold until the effects are fully assessed, and measures are taken to mitigate further risks. All areas and facilities that had been used to administer the product would be cleaned and decontaminated using agents effective against adenoviruses.

REFERENCES 1. Abbink P., et al., Comparative seroprevalence and immunogenicity of six rare serotype

recombinant adenovirus vaccine vectors from subgroups B and D. J Virol, 2007. 81(9): p. 4654-63. 2. Fallaux F. J., et al., New helper cells and matched early region 1-deleted adenovirus vectors prevent

generation of replication-competent adenoviruses. Hum Gene Ther, 1998. 9(13): p. 1909-17. 3. Sheets R.L., et al, Biodistribution and toxicological safety of adenovirus type 5 and type 35

vectored vaccines against human immunodeficiency virus-1 (HIV-1), Ebola, or Marburg are similar despite differing adenovirus serotype vector, manufacturer's construct, or gene inserts. J Immunotoxicol, 2008. 5(3): p. 315-35.

4. Baden LR, Karita, E, Mutua, G, Bekker, LG, Gray, G, Page-Shipp L, et al. , Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention: A Randomized Trial. Ann Intern Med., 2016. 164(313-322).


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5. Baden LR, Walsh, SR, Seaman, MS, et al., First-in-human evaluation of the safety and immunogenicity of a recombinant adenovirus serotype 26 HIV-1 Env vaccine (IPCAVD 001). . J Infect Dis., 2013. 207: p. 240-247.

6. Barouch DH Tomaka FL, Wegmann F, et al. , Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). . Lancet, 2018. 392(10143): p. 232-243.

7. Mast TC Kierstead L, Gupta SB, et al, International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: correlates of high Ad5 titers and implications for potential HIV vaccine trials. . Vaccine, 2010. 28(4): p. 950-957.

8. Vogels R Zuijdgeest D, van Rijnsoever R, et al., Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity. J Virol, 2003. 77: p. 8263-8271.

9. Public Health Agency of Canada. Adenovirus types 1, 2, 3, 4, 5 and 7 - Pathogen Safety Data Sheet. . 18 May 2017]; Available from: http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/msds3e-eng.php.

10. Health and Safety Executive. The SACGM Compendium of Guidance. 05 Sep 2018]; Available from: http://www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/part2.pdf.

11. Keefer MC Gilmour J, Hayes P, et al. , A phase I double blind, placebo-controlled, randomized study of a multigenic HIV-1 adenovirus subtype 35 vector vaccine in healthy uninfected adults. . PLoS One, 2012. 7(8): p. e41936.

http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/msds3e-eng.php

http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/msds3e-eng.php

http://www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/part2.pdf

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