Broadly neutralizing DNA vaccine with specific mutation alters the antigenicity and sugar-binding activities of influenza hemagglutinin

Chen, Ming-Wei; Liao, Hsin-Kai; Huang, Yaoxing; Jan, Jia-Tsrong; Huang, Chih-Cheng; Ren, Chien‐Tai; Wu, Chung‐Yi; Cheng, Ting‐Jen R.; Ho, David D.; Wong, Chi‐Huey

doi:10.1073/pnas.1019744108

Cited by 19 publications

(13 citation statements)

References 43 publications

(44 reference statements)

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“…The generation of "centralized" vaccine immunogens has been proven to be an effective method to reduce the genetic distances between the vaccine immunogen and the contemporary virus strains circulating in the field, thereby expanding vaccine coverage (31,32). Thus far, centralized vaccine immunogens are commonly generated based on the amino acid sequences of selected viral proteins (34)(35)(36)(37)69). In the case of PRRSV, the viral proteins that are involved in eliciting protective immunity are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…A consensus sequence that carries the most common amino acid found at each position of the alignment is the simplest method for the construction of a centralized immunogen (31). Studies on HIV-1 and influenza virus have clearly demonstrated that vaccines based on the consensus sequences elicit broader immune responses than do vaccines based on naturally occurring sequences (34)(35)(36)(37)(38).…”

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confidence: 99%

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A Synthetic Porcine Reproductive and Respiratory Syndrome Virus Strain Confers Unprecedented Levels of Heterologous Protection

Laegreid

et al. 2015

J Virol

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Current vaccines do not provide sufficient levels of protection against divergent porcine reproductive and respiratory syndrome virus (PRRSV) strains circulating in the field, mainly due to the substantial variation of the viral genome. We describe here a novel approach to generate a PRRSV vaccine candidate that could confer unprecedented levels of heterologous protection against divergent PRRSV isolates. By using a set of 59 nonredundant, full-genome sequences of type 2 PRRSVs, a consensus genome (designated PRRSV-CON) was generated by aligning these 59 PRRSV full-genome sequences, followed by selecting the most common nucleotide found at each position of the alignment. Next, the synthetic PRRSV-CON strain was generated through the use of reverse genetics. PRRSV-CON replicates as efficiently as our prototype PRRSV strain FL12, both in vitro and in vivo. Importantly, when inoculated into pigs, PRRSV-CON confers significantly broader levels of heterologous protection than does wild-type PRRSV. Collectively, our data demonstrate that PRRSV-CON can serve as an excellent candidate for the development of a broadly protective PRRSV vaccine. IMPORTANCEThe extraordinary genetic variation of RNA viruses poses a monumental challenge for the development of broadly protective vaccines against these viruses. To minimize the genetic dissimilarity between vaccine immunogens and contemporary circulating viruses, computational strategies have been developed for the generation of artificial immunogen sequences (so-called "centralized" sequences) that have equal genetic distances to the circulating viruses. Thus far, the generation of centralized vaccine immunogens has been carried out at the level of individual viral proteins. We expand this concept to PRRSV, a highly variable RNA virus, by creating a synthetic PRRSV strain based on a centralized PRRSV genome sequence. This study provides the first example of centralizing the whole genome of an RNA virus to improve vaccine coverage. This concept may be significant for the development of vaccines against genetically variable viruses that require active viral replication in order to achieve complete immune protection. P orcine reproductive and respiratory syndrome (PRRS) is widespread in most swine-producing countries worldwide, causing significant economic losses to swine producers. In the United States alone, the disease causes approximately $664 million in losses to American swine producers annually (1). Clinical signs of PRRS include reproductive failure in pregnant sows and respiratory diseases in young pigs. The causative agent of PRRS is a positive-sense, single-stranded RNA virus that belongs to the family Arteriviridae of the order Nidovirales and is referred to as porcine reproductive and respiratory syndrome virus (PRRSV) (2-4). The PRRSV genome is ϳ15 kb in length and encodes at least 22 different viral proteins (5). Several viral proteins have been shown to elicit humoral and/or cell-mediated immune responses in infected pigs, but none of those proteins have be...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A Synthetic Porcine Reproductive and Respiratory Syndrome Virus Strain Confers Unprecedented Levels of Heterologous Protection

Laegreid

et al. 2015

J Virol

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“…Human immunodeficiency virus cores are derived from several different origins between laboratory groups. First generation pNL4-3 vectors are well represented and the pNL4-3-Luc.E-Rvariant is the most commonly used (9)(10)(11)(12)(13)(14). The pNL4-3.Luc.E-Rreplication deficient proviral HIV-1 clone is derived from the pNL precursor but has inhibitory frame shifts in the env and vpr genes as well as a luciferase reporter gene cloned into nef and the entire construct is incorporated into progeny pseudotypes.…”

Section: Retroviral and Lentiviral Cores And Vectorsmentioning

confidence: 99%

“…This process is the basis on which influenza neutralization assays are founded -the exploitation of attachment and entry for the study of HA-directed antibodies and their neutralizing ability. Analysis has permitted classification of influenza A subtypes into two distinct groups: group 1 containing subtypes 1,2,5,6,8,9,11,12,13,16,17, and 18 and group 2 containing 3, 4, 7, 10, 14, and 15 (62)(63)(64). Subtypes within each group are often subdivided into clades with further sequence dissimilarity.…”

Section: Influenza Envelope Proteins: Hemagglutininmentioning

confidence: 99%

Pseudotype-Based Neutralization Assays for Influenza: A Systematic Analysis

et al. 2015

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The use of vaccination against the influenza virus remains the most effective method of mitigating the significant morbidity and mortality caused by this virus. Antibodies elicited by currently licensed influenza vaccines are predominantly hemagglutination-inhibition (HI)-competent antibodies that target the globular head of hemagglutinin (HA) thus inhibiting influenza virus entry into target cells. These antibodies predominantly confer homosubtypic/strain specific protection and only rarely confer heterosubtypic protection. However, recent academia or pharma-led R&D toward the production of a “universal vaccine” has centered on the elicitation of antibodies directed against the stalk of the influenza HA that has been shown to confer broad protection across a range of different subtypes (H1–H16). The accurate and sensitive measurement of antibody responses elicited by these “next-generation” influenza vaccines is, however, hampered by the lack of sensitivity of the traditional influenza serological assays HI, single radial hemolysis, and microneutralization. Assays utilizing pseudotypes, chimeric viruses bearing influenza glycoproteins, have been shown to be highly efficient for the measurement of homosubtypic and heterosubtypic broadly neutralizing antibodies, making them ideal serological tools for the study of cross-protective responses against multiple influenza subtypes with pandemic potential. In this review, we will analyze and compare literature involving the production of influenza pseudotypes with particular emphasis on their use in serum antibody neutralization assays. This will enable us to establish the parameters required for optimization and propose a consensus protocol to be employed for the further deployment of these assays in influenza vaccine immunogenicity studies.

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“…There was a clear positive relationship between net charge change of substitutions and avidity, retroactively consistent with a prior study on H3 escape mutants [26] (interestingly, epidemic H3 (but not H1 viruses) demonstrate a clear increase in net positive charge during their first 20 years evolution in humans [27]). Similarly, single amino acid substitutions in the major antigenic sites of the H5 HA were shown to modulate receptor avidity [28,29] and immune escape in VN and HI assays [29]. Selection of adsorptive mutants is likely to be relevant for other pathogens subject to antibody competition for attachment, and should be relatively easy to detect in highly variable viruses like norovirus, which demonstrate rapid antigenic drift in humans [30].…”

Section: Rethinking Driftmentioning

confidence: 99%

Viva la revolución: rethinking influenza A virus antigenic drift

Yewdell

2011

Current Opinion in Virology

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Rapid antigenic evolution of the influenza A virus hemagglutinin has precluded developing vaccines that provide durable protection. The yearly costs of influenza (circa $1011 in the USA alone) easily justify investments in better understanding the interaction of influenza with antibodies and other inducible elements of the immune system that potentially limit or circumvent antigenic variation. Here, I summarize exciting new findings that offer the possibility of a quantum improvement in vaccine efficacy, focusing on studies clearly documenting robust neutralizing antibody responses to the conserved stem region of the hemagglutinin.

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Broadly neutralizing DNA vaccine with specific mutation alters the antigenicity and sugar-binding activities of influenza hemagglutinin

Cited by 19 publications

References 43 publications

A Synthetic Porcine Reproductive and Respiratory Syndrome Virus Strain Confers Unprecedented Levels of Heterologous Protection

A Synthetic Porcine Reproductive and Respiratory Syndrome Virus Strain Confers Unprecedented Levels of Heterologous Protection

Pseudotype-Based Neutralization Assays for Influenza: A Systematic Analysis

Viva la revolución: rethinking influenza A virus antigenic drift

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