Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function

Monoclonal antibodies (mAbs) are now considered as a therapeutic approach to prevent and treat severe viral infections. Using a mouse retroviral model, we showed that mAbs induce protective immunity (vaccinal effects). Here, we investigated the role of natural killer (NK) cells on this effect. NK cells are effector cells that are crucial to control viral propagation upon mAb treatment. However, their immunomodulatory activity during antiviral mAb immunotherapies has been little studied. Our data reveal that the mAb treatment of infected mice preserves the functional activation of NK cells. Importantly, functional NK cells play an essential role in preventing immune dysfunction and inducing antiviral protective immunity upon mAb therapy. Thus, NK cell depletion in mAb-treated, viral-infected mice leads to the upregulation of molecules involved in immunosuppressive pathways (i.e., PD-1, PD-L1 and CD39) on dendritic cells and T cells. NK cell depletion also abrogates the vaccinal effects induced by mAb therapy. Our data also reveal a role for IFNγ-producing NK cells in the enhancement of the B-cell responses through the potentiation of the B-cell helper properties of neutrophils. These findings suggest that preserved NK cell functions and counts might be required for achieving mAb-induced protective immunity. They open new prospects for improving antiviral immunotherapies.

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Role of NK Cells during Antiviral Antibody Therapy

Naranjo-Gómez¹,

Cahen²,

Lambour³

et al. 2021

“…By contrast, antibodies with RBS-blocking activity tend to induce less robust ADCC responses [ 115 , 116 , 117 , 118 ]. Nevertheless, antibody neutralization and induction of ADCC are not mutually exclusive and can operate synergistically [ 106 , 119 , 120 ]. Such synergy may also be balanced by antibody-dependent enhancement risks, such as enhanced infection of monocytes and myeloid dendritic cells as reported for anti-HA antibodies from macaques [ 121 ].…”

Section: Functionally Conserved Antibody Targets On Influenza Hemamentioning

confidence: 99%

Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for ‘Universal’ Influenza Vaccines

Sangesland

Lingwood

2021

Influenza virus remains a serious public health burden due to ongoing viral evolution. Vaccination remains the best measure of prophylaxis, yet current seasonal vaccines elicit strain-specific neutralizing responses that favor the hypervariable epitopes on the virus. This necessitates yearly reformulations of seasonal vaccines, which can be limited in efficacy and also shortchange pandemic preparedness. Universal vaccine development aims to overcome these deficits by redirecting antibody responses to functionally conserved sites of viral vulnerability to enable broad coverage. However, this is challenging as such antibodies are largely immunologically silent, both following vaccination and infection. Defining and then overcoming the immunological basis for such subdominant or ‘immuno-recessive’ antibody targeting has thus become an important aspect of universal vaccine development. This, coupled with structure-guided immunogen design, has led to proof-of-concept that it is possible to rationally refocus humoral immunity upon normally ‘unseen’ broadly neutralizing antibody targets on influenza virus.

“…The cross-linkage among the antigen, antibody and the effector cells triggers immune effector functions, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC), which contribute to the clearance of virus-infected cells and virus particles (ADCP particularly) ( Figure 2 C). Many sources of evidence have shown that effector functions mediated by antibodies are critical for protection against influenza virus, human immunodeficiency virus and respiratory syncytial virus [ 117 , 118 , 119 ]. In addition, ADCC antibodies are associated with the clinical presentation of neonatal herpes simplex virus (HSV) infection [ 120 ] and are protective against HSV-1 and -2 in a mouse model of maternal immunization [ 121 ].…”

Section: Mda Interference: a Major Bottleneck For Ndv-vectored Vacmentioning

confidence: 99%

Newcastle Disease Virus as a Vaccine Vector for 20 Years: A Focus on Maternally Derived Antibody Interference

Cao

et al. 2020

It has been 20 years since Newcastle disease virus (NDV) was first used as a vector. The past two decades have witnessed remarkable progress in vaccine generation based on the NDV vector and optimization of the vector. Protective antigens of a variety of pathogens have been expressed in the NDV vector to generate novel vaccines for animals and humans, highlighting a great potential of NDV as a vaccine vector. More importantly, the research work also unveils a major problem restraining the NDV vector vaccines in poultry, i.e., the interference from maternally derived antibody (MDA). Although many efforts have been taken to overcome MDA interference, a lack of understanding of the mechanism of vaccination inhibition by MDA in poultry still hinders vaccine improvement. In this review, we outline the history of NDV as a vaccine vector by highlighting some milestones. The recent advances in the development of NDV-vectored vaccines or therapeutics for animals and humans are discussed. Particularly, we focus on the mechanisms and hypotheses of vaccination inhibition by MDA and the efforts to circumvent MDA interference with the NDV vector vaccines. Perspectives to fill the gap of understanding concerning the mechanism of MDA interference in poultry and to improve the NDV vector vaccines are also proposed.