Feline immunodeficiency virus (FIV) vaccine efficacy and FIV neutralizing antibodies

ABSTRACT Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8+ T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8+ T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.

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Simple in vitro methods for titrating Feline Immunodeficiency Virus (FIV) and FIV neutralizing antibodies

Journal of Virological Methods ◽

10.1016/0166-0934(92)90026-a ◽

1992 ◽

Vol 37 (3) ◽

pp. 241-252 ◽

Cited By ~ 23

Author(s):

Franco Tozzini ◽

Donatella Matteucci ◽

Patrizia Bandecchi ◽

Fulvia Baldinotti ◽

Alessandro Poli ◽

...

Keyword(s):

Feline Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

In Vitro Methods ◽

Immunodeficiency Virus

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Role of Env in Resistance of Feline Immunodeficiency Virus (FIV)-Infected Cats to Superinfection by a Second FIV Strain as Determined by Using a Chimeric Virus

Journal of Virology ◽

10.1128/jvi.01064-07 ◽

2007 ◽

Vol 81 (19) ◽

pp. 10474-10485 ◽

Cited By ~ 4

Author(s):

Simone Giannecchini ◽

Mauro Pistello ◽

Patrizia Isola ◽

Donatella Matteucci ◽

Paola Mazzetti ◽

...

Keyword(s):

Feline Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Viral Envelope ◽

Lymphoid Cells ◽

Time Interval ◽

Complete Protection ◽

Challenge Virus ◽

Immunodeficiency Virus

ABSTRACT A more or less pronounced resistance to superinfection by a second strain of the infecting virus has been observed in many lentivirus-infected hosts. We used a chimeric feline immunodeficiency virus (FIV), designated FIVχ, containing a large part of the env gene of a clade B virus (strain M2) and all the rest of the genome of a clade A virus (a p34TF10 molecular clone of the Petaluma strain modified to grow in lymphoid cells), to gain insights into such resistance. FIVχ was infectious and moderately pathogenic for cats and in vitro exhibited the neutralization specificity of the env donor. The experiments performed were bidirectional, in that cats preinfected with either parental virus were challenged with FIVχ and vice versa. The preinfected animals were partially or completely protected relative to what was observed in naïve control animals, most likely due, at least in part, to the circumstance that in all the preinfecting/challenge virus combinations examined, the first and the second virus shared significant viral components. Based on the proportions of complete protection observed, the role of a strongly matched viral envelope appeared to be modest and possibly dependent on the time interval between the first and the second infection. Furthermore, complete protection and the presence of measurable neutralizing antibodies capable of blocking the second virus in vitro were not associated.

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Env-Expressing Autologous T Lymphocytes Induce Neutralizing Antibody and Afford Marked Protection against Feline Immunodeficiency Virus

Journal of Virology ◽

10.1128/jvi.02638-09 ◽

2010 ◽

Vol 84 (8) ◽

pp. 3845-3856 ◽

Cited By ~ 8

Author(s):

Mauro Pistello ◽

Francesca Bonci ◽

Elisa Zabogli ◽

Francesca Conti ◽

Giulia Freer ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Feline Immunodeficiency Virus ◽

Cd4 T Cells ◽

Neutralizing Antibodies ◽

Ex Vivo ◽

Neutralizing Antibody ◽

Viral Loads ◽

Immunodeficiency Virus ◽

Specific Pathogen

ABSTRACT The envelope (Env) glycoproteins of HIV and other lentiviruses possess neutralization and other protective epitopes, yet all attempts to induce protective immunity using Env as the only immunogen have either failed or afforded minimal levels of protection. In a novel prime-boost approach, specific-pathogen-free cats were primed with a plasmid expressing Env of feline immunodeficiency virus (FIV) and feline granulocyte-macrophage colony-stimulating factor and then boosted with their own T lymphocytes transduced ex vivo to produce the same Env and interleukin 15 (3 × 106 to 10 × 106 viable cells/cat). After the boost, the vaccinees developed elevated immune responses, including virus-neutralizing antibodies (NA). Challenge with an ex vivo preparation of FIV readily infected all eight control cats (four mock vaccinated and four naïve) and produced a marked decline in the proportion of peripheral CD4 T cells. In contrast, five of seven vaccinees showed little or no traces of infection, and the remaining two had reduced viral loads and underwent no changes in proportions of CD4 T cells. Interestingly, the viral loads of the vaccinees were inversely correlated to the titers of NA. The findings support the concept that Env is a valuable immunogen but needs to be administered in a way that permits the expression of its full protective potential.

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Vaccination protects against in vivo-grown feline immunodeficiency virus even in the absence of detectable neutralizing antibodies.

Journal of Virology ◽

10.1128/jvi.70.1.617-622.1996 ◽

1996 ◽

Vol 70 (1) ◽

pp. 617-622 ◽

Cited By ~ 34

Author(s):

D Matteucci ◽

M Pistello ◽

P Mazzetti ◽

S Giannecchini ◽

D Del Mauro ◽

...

Keyword(s):

Feline Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Immunodeficiency Virus

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Vaccination with Inactivated Virus but Not Viral DNA Reduces Virus Load following Challenge with a Heterologous and Virulent Isolate of Feline Immunodeficiency Virus

Journal of Virology ◽

10.1128/jvi.74.20.9403-9411.2000 ◽

2000 ◽

Vol 74 (20) ◽

pp. 9403-9411 ◽

Cited By ~ 37

Author(s):

Margaret J. Hosie ◽

Thomas Dunsford ◽

Dieter Klein ◽

Brian J. Willett ◽

Celia Cannon ◽

...

Keyword(s):

Feline Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Complete Protection ◽

Virus Load ◽

Virus Particles ◽

Virulent Isolate ◽

Load Following ◽

Immunodeficiency Virus ◽

Attenuated Isolate

ABSTRACT It has been shown that cats can be protected against infection with the prototypic Petaluma strain of feline immunodeficiency virus (FIVPET) using vaccines based on either inactivated virus particles or replication-defective proviral DNA. However, the utility of such vaccines in the field is uncertain, given the absence of consistent protection against antigenically distinct strains and the concern that the Petaluma strain may be an unrepresentative, attenuated isolate. Since reduction of viral pathogenicity and dissemination may be useful outcomes of vaccination, even in the absence of complete protection, we tested whether either of these vaccine strategies ameliorates the early course of infection following challenge with heterologous and more virulent isolates. We now report that an inactivated virus vaccine, which generates high levels of virus neutralizing antibodies, confers reduced virus loads following challenge with two heterologous isolates, FIVAM6 and FIVGL8. This vaccine also prevented the marked early decline in CD4/CD8 ratio seen in FIVGL8-infected cats. In contrast, DNA vaccines based on either FIVPET or FIVGL8, which induce cell-mediated responses but no detectable antiviral antibodies, protected a fraction of cats against infection with FIVPET but had no measurable effect on virus load when the infecting virus was FIVGL8. These results indicate that the more virulent FIVGL8 is intrinsically more resistant to vaccinal immunity than the FIVPET strain and that a broad spectrum of responses which includes virus neutralizing antibodies is a desirable goal for lentivirus vaccine development.

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AIDS Vaccination Studies Using an Ex Vivo Feline Immunodeficiency Virus Model: Reevaluation of Neutralizing Antibody Levels Elicited by a Protective and a Nonprotective Vaccine after Removal of Antisubstrate Cell Antibodies

Journal of Virology ◽

10.1128/jvi.75.9.4424-4429.2001 ◽

2001 ◽

Vol 75 (9) ◽

pp. 4424-4429 ◽

Cited By ~ 10

Author(s):

Simone Giannecchini ◽

Daniela Del Mauro ◽

Donatella Matteucci ◽

Mauro Bendinelli

Keyword(s):

Infected Cell ◽

Feline Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Ex Vivo ◽

Neutralizing Antibody ◽

Cell Vaccine ◽

Immunodeficiency Virus ◽

Fixed Cell ◽

Antibody Levels

ABSTRACT In the feline immunodeficiency virus system, immunization with a fixed-infected-cell vaccine conferred protection against virulent homologous challenge but the immune effectors involved remained elusive. In particular, few or no neutralizing antibodies were detected in sera from vaccinated cats. Here we show that, when preadsorbed with selected feline cells, the same sera revealed clearly evident virus-neutralizing activity. Because high titers of neutralizing antibody in cell-adsorbed sera from 23 cats immunized with fixed-infected-cell or whole-inactivated-virus vaccines correlated with protection, it is likely that they were more important for protection than formerly realized. In vitro, the fixed-cell vaccine efficiently removed neutralizing antibody from immune sera while the whole-inactivated-virus vaccine was much less effective.

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Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Clinical and Vaccine Immunology ◽

10.1128/cvi.00230-14 ◽

2014 ◽

Vol 21 (8) ◽

pp. 1023-1036 ◽

Cited By ~ 68

Author(s):

Jean-Louis Excler ◽

Julie Ake ◽

Merlin L. Robb ◽

Jerome H. Kim ◽

Stanley A. Plotkin

Keyword(s):

Human Immunodeficiency Virus ◽

Vaccine Efficacy ◽

Neutralizing Antibodies ◽

Hiv Vaccine ◽

Antibody Responses ◽

Effector Functions ◽

Efficacy Trials ◽

Immunodeficiency Virus ◽

Specific Igg ◽

Hiv Acquisition

ABSTRACTAnimal and human data from various viral infections and vaccine studies suggest that nonneutralizing antibodies (nNAb) without neutralizing activityin vitromay play an important role in protection against viral infectionin vivo. This was illustrated by the recent human immunodeficiency virus (HIV) RV144 vaccine efficacy trial, which demonstrated that HIV-specific IgG-mediated nNAb directed against the V2 loop of HIV type 1 envelope (Env) were inversely correlated with risk for HIV acquisition, while Env-specific plasma IgA-mediated antibodies were directly correlated with risk. However, tier 1 NAb in the subset of responders with a low level of plasma Env-specific IgA correlated with decreased risk. Nonhuman primate simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) challenge studies suggest that Env-mediated antibodies are essential and sufficient for protection. A comparison of immune responses generated in human efficacy trials reveals subtle differences in the fine specificities of the antibody responses, in particular in HIV-specific IgG subclasses. The underlying mechanisms that may have contributed to protection against HIV acquisition in humans, although not fully understood, are possibly mediated by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or other nonneutralizing humoral effector functions, such as antibody-mediated phagocytosis. The presence of such functional nNAb in mucosal tissues and cervico-vaginal and rectal secretions challenges the paradigm that NAb are the predominant immune response conferring protection, although this does not negate the desirability of evoking neutralizing antibodies through vaccination. Instead, NAb and nNAb should be looked upon as complementary or synergistic humoral effector functions. Several HIV vaccine clinical trials to study these antibody responses in various prime-boost modalities in the systemic and mucosal compartments are ongoing. The induction of high-frequency HIV-specific functional nNAb at high titers may represent an attractive hypothesis-testing strategy in future HIV vaccine efficacy trials.

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