Defective adenoviruses as virus vectors for veterinary vaccines

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Defective adenoviruses as virus vectors for veterinary vaccines

M. Eloit

To cite this version:

M. Eloit. Defective adenoviruses as virus vectors for veterinary vaccines. Veterinary Research, BioMed

Central, 1995, 26 (3), pp.207-208. �hal-02699483�

(

1 ^{INRA, unité de} virologie ^et d’immunologie moléculaires, domaine de Vilvert, ⁷⁸³⁵²

Jouy-en-Josas; ^{2 CNEVA, unité de} patho- logie cunicole, ²²⁴⁴⁰ Ploufragan, France)

Le syndrome hémorragique ^{viral du} lapin (RHDV) ^a pour agent ^{causal un} calicivirus, virus dont la capside résulte de la multimé- risation d’une seule protéine, Vp60. ^{En rai-}

son de l’absence de système de culture du virus, les vaccins inactivés ont été jusqu’à présent préparés ^à partir de foies d’animaux infectés.

Le choix d’une stratégie vaccinale repo- sant sur l’utilisation de Vp60 recombinante

permettait de résoudre plusieurs problèmes :

-

obtention de préparations antigéniques

en quantité importante, homogènes ^{et aisé-}

ment purifiables ;

-

absence de pathogénicité résiduelle ;

-

démonstration du rôle de la Vp60 ^dans

l’induction d’une protection.

Le système Baculovirus/Sfg ^s’est imposé

par ^sa simplicité ^{et ses} qualités ^comme pre- mier système d’expression pour la Vp60 ^du

virus RHVD. La Vp60 produite ^en grande quantité par les baculovirus recombinants

se multimérise pour former des pseudo-par-

ticules (VLP) morphologiquement identiques

aux virions (Laurent ^{et al,} 1994).

L’utilisation de ces VLP dans

essai de vaccination par voie parentérale ^{a mon-}

tré une efficacité égale à celle des prépa-

rations commerciales. Ayant validé l’utilisa- tion de la Vp60 recombinante pour la vaccination des animaux contre la RHVD,

nous collaborons avec l’équipe ^{d’A Milon} (ENV Toulouse) pour l’obtention d’un ^vaccin recombinant Myxomatose/RHVD.

Référence

Laurent S, Vautherot JF, Madelaine MF, Le Gall G, Rasschaert D (1994) Recombinant rabbit hemor-

rhagic disease ^virus capsid protein expressed ⁱⁿ baculovirus self-assembles into viruslike particles and induces protection. J Virol68, ^6794-6798

Defective adenoviruses as virus vectors for veterinary vaccines. M M Éloit (INRA, Éloit (INRA, École nationale vétérinaire dalfort, ^{unité de} génétique moléculaire-génétique ^virale,

94701 Maisons-Alfort, France)

We are studying ^the potency ^{and the} safety

of replication defective Ad5-based vectors

(E1A defective) for the vaccination of ani- mals. Use of replication defective aden- oviruses can be compared ^to genetic ^immu-

nisation. In both _cases, the foreign gene ^is persistent ^{for a} long ^time, during ^{which its} product ^is correctly presented ^{to the immune} system ⁱⁿ association with the CMH. This

approach ^{leads to some} advantages (biosafety, adequate processing of the anti- gen, long-lasting immune response ^and induction of a mucosal immunity). ^{Ad5 wild-} type ^{is able to} replicate ^at high titre in human cells and at medium titres in Vero (monkey),

GBK22 (bovine) ^{and PK15} (pig) cell lines. It does not replicate ^{in MDCK3} (canine),

G355-5 (feline) ^{and 3T3} (murine) cell lines.

Nevertheless, Ad5 vectors can introduce

foreign genes in vitro into all these cell lines, and

into avian and fish cells, showing

that the virus cycle is abortive at a step ^fol- lowing ^the penetration of the virion and the

decapsidation of the DNA. A number of mammalian species (eg, ^{mouse, rat, cattle,} pig, dog ^and cat) ^{and even chickens can}

mount an immune response against ^{a for-} eign protein inserted in Ad5 vectors. Nasal, muscular and subcutaneous routes are effi- cient methods of administration in mice, while the oral route proved ^to be inefficient in this species. Intraduodenal administra- tion in pigs (a ^first step of evaluation of

gastroprotected preparations) ^{led to the}

development ^{of a low} antibody response,

whereas the mucosal immunity ^{was not}

evaluated.

Immunity ^conferred by Ad-vectored vac-

cines seems to be long-lasting (at ^{least 8}

months after a unique injection ^{in adult or} 1-day-old mice). ^Some drawbacks still exist, for example ^{the need to inoculate a} high

level of virus in order to elicit a strong

immune response (10 $ ^{to 10 9} TCID 50 )- Nevertheless, ^we have shown that the pro- tective doses in mice were greatly ^reduced

when the virus was formulated in oil adju-

vants. Moreover, ^our recent work showed that the simultaneous inoculation of a recom-

binant adenovirus and a plasmid coding ^for

IL2 by the intramuscular route led to an

enhancement of the immune response. We have also compared protective ^{doses of an} Ad-gD, ^a replication-defective ^adenovirus expressing ^the gD gene of pseudorabies virus, ^and Ad-gD-E1 a, ^{in which a functional}

E1 A transcription unit has been restored.

The protective ^{dose of} Ad-gD-E1a ^was

1 000-fold lower in cotton-rats, ^an Ad5 per- missive species, than that of Ad-gD. ^{In mice,}

a species restricted for Ad5 replication, ^the protective ^{dose of} Ad-gD-E1 ^{a was still 16-}

fold lower than that of Ad-gD. ^{In both} species, Ad-gD ^and Ad-gD-E1 ^{a induced}

similar antibody responses for each dose tested. Recently, experiments ⁱⁿ pigs ^with

oil-formulated Ad-gD ^showed good ^evidence

of efficacy, ^{close to that of} adjuvanted ^live

vaccines which express all the glycoproteins

of PRV.

We are also investigating ^one of the main limitations of vaccination of new-born chil- dren or animals, ie the interference of mater- nal antibodies. Experiments ^are currently being ^{conducted in mice and} pigs by injec-

tion of naked DNA or recombinant adeno-

virus, ^each expressing gD ^{under the con-}

trol of the same regulatory sequences, ^to litters of mothers vaccinated or not against

PRV. Several trials are currently being

undertaken or planned, ^{to evaluate recom-}

binant viruses expressing genes from PRV,

FIV, ^FIP and canine distemper viruses inoc- ulated by ^{various routes.} On the other hand, several experiments ^{have been} or are cur-

rently being ^{carried out to} evaluate the safety

of replication defective adenoviruses. First, the dissemination of deletion mutants of Ad5 and wt virus was evaluated in cotton rats and mice (respectively permissive ^{and non-} permissive ^for wild-type Ad5), using ^several

routes of administration. Secondly, ^cotton

rats were coinoculated with 2 recently ^con-

structed defective adenoviruses express-

ing either the betagalactosidase ^{or the}

luciferase gene, by the intramuscular or the intravenous route and later infected with a wt Ad5. No transcomplementation ^{of the defec-}

tive E1a/E1b genes ^was evidenced in vivo, in contrast with in vitro experiments. ^{We are}

also studying ^the capacity of the E1 gene of several animal adenoviruses to provide phenotypic transcomplementation ^{of their} counterparts ^{in Ad5.} Finally, several modi- fications of the encaspidation signals ^are being made in order to design ^adenovirus

genome vectors with reduced ability ^{to be} encapsided when mixed with a wt virus.

Bibliography

!loit M, Gilardi-Hebenstreit P, Toma B, Perricaudet M

(1990) Construction of

defective adenovirus vector

expressing ^the pseudorabies ^virus glycoprotein gp50 and its

live vaccine. J Gen Virol 71, 2425- 2431

Ganne V, !loit M, Laval A, Adam M, ^{Trouve G} (1994)

Enhancement of the efficacy ^of

replication ^defec- tive adenovirus vectored vaccine by ^{the addition of} oil adjuvants. Vaccine 12, 1190-1196

Oualikene 0, ^Gonin P, !loit M (1994) Short- and long-

term dissemination of deletion mutants of adenovirus in permissive (cotton rat) ^and non-permissive (mouse) species. ^{J Gen} Virol75, ^2765-2768

Pseudo particules de rotavirus : pro-

priétés ^et perspectives d’utilisation. J J Cohen A Charpilienne ^{M Labbé S}

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