Designing Tomorrow's Vaccines Nabel, Gary J
New England journal of medicine/The New England journal of medicine,
02/2013, Volume:
368, Issue:
6
Journal Article
Peer reviewed
Open access
Vaccines are some of the most cost-effective treatments in medicine. This article reviews new strategies being applied to develop vaccines for diseases that have not been susceptible to this ...therapeutic approach.
Vaccines are among the most effective interventions in modern medicine. Ever since Edward Jenner's first use of a vaccine against smallpox in 1796 (see text box), the use of vaccines has become indispensable to the eradication of disease. In the 20th century alone, smallpox claimed an estimated 375 million lives, but since 1978, after the completion of a successful eradication campaign, not a single person has died from smallpox. Today, more than 70 vaccines have been licensed for use against approximately 30 microbes, sparing countless lives (Figure 1A and 1B).
1
,
2
Diseases including poliomyelitis, measles, mumps, rubella, and others caused an estimated . . .
Vaccines are some of the most cost-effective treatments in medicine. This article reviews new strategies being applied to develop vaccines for diseases that have not been susceptible to this ...therapeutic approach.
The field of HIV-1 vaccine research has seen a renaissance with the identification of antibodies that neutralize most circulating HIV-1 strains. An understanding of the structural mode of target ...recognition that these antibodies use and the immune pathways that lead to their development is emerging. This knowledge has provided fundamental insights into the pathways that elicit broadly neutralizing antibodies and provides a foundation for active and passive immunization strategies to prevent HIV-1 infection.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major ...target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses.
Display omitted
Display omitted
•Self-assembling nanoparticles present the conserved gp350 receptor-binding domain•The nanoparticles elicit more potent neutralizing antibodies than soluble gp350•These neutralizing antibodies predominantly target the CR2-binding site on gp350•The nanoparticles elicit potent neutralizing antibodies in mice and non-human primates
Structurally designed EBV vaccine candidates based on self-assembling nanoparticles elicit potent and durable virus-neutralizing antibodies that target the receptor-binding site on the viral envelope protein gp350, a site of vulnerability, serving as a template to develop an EBV vaccine and providing a basis for immunofocusing through rational vaccine design.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic ...agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar(-/-) ) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide, ultimately the consequence of cytolytic infection of CD4(+) T cells. In ...humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia, yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4(+) T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4(+) T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The immune system normally responds to influenza virus by making neutralizing antibodies to regions of the viral spike, the hemagglutinin, that vary year to year. This natural response protects ...against circulating subtypes but necessitates production of new vaccines annually. Newer vaccine approaches have succeeded in eliciting broadly neutralizing antibodies to highly conserved yet vulnerable regions of the hemagglutinin and suggest potential pathways for the development of universal influenza vaccines.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Participants at the February 2011 meeting at the U.S. National Institutes of Health on Epstein-Barr virus (EBV) vaccine research recommend that future clinical trials have two goals: prevention of ...infectious mononucleosis and EBV-associated cancers, facilitated by identification of disease-predictive surrogate markers.
Patents, economics, and pandemics Zerhouni, Will; Nabel, Gary J; Zerhouni, Elias
Science (American Association for the Advancement of Science),
2020-Jun-05, 2020-06-05, 20200605, Volume:
368, Issue:
6495
Journal Article
Peer reviewed
As coronavirus disease 2019 (COVID-19) has quickly killed hundreds of thousands across an unprepared world, destroyed the livelihoods of millions, and cost trillions of dollars, nations must now ...expand their mindsets and focus not only on overcoming the next phases but also on long-range strategies—for this and for future pandemics. The world needs a permanent preparedness enterprise to engage in a sustained effort to avert pandemics, and provide for the affordable and widespread administration of vaccines and therapies when they are discovered.
PDF
