Ciencias Exactas y Ciencias de la Salud

In the last two decades, there have been very important epidemic (and pandemic) episodes related to viral infections in humans. These diseases have caused millions of deaths. The main viruses that have been affected to humans are Ebola, Influenza, Zika, Dengue, and Coronavirus. In this thesis project, we have focused on three viral agents that have caused epidemic (or pandemic episodes) recently: the Ebola, Zika and SARS-CoV-2 viruses. We describe the developing of diagnostic techniques, and the design and production of recombinant proteins with application for treatment or vaccination. Throughout the following chapters, each one corresponding to a manuscript that has been already submitted for publication, we pay particular attention to discuss the context of relevance and the rational of design of each development. The phocus of each one of this designs is engineering rational and cost-effective solutions (as referred in the tittle) to face epidemic events such as the one that we are currently experiencing. Next, we briefly introduce the context of each one of the viral agents that we take as models. The Ebola virus has infected more than 28,000 people in recent years, leading to more than 11,000 deaths. The Ebola disease (EBOV) is associated to a fatality rate that has reached 90% but is currently around 50%. This virus has been one of the most aggressive in history, and until a few months ago, there was no approved treatment or vaccine to be administered to patients. Recently, the FDA approved the first treatment and vaccine: Inmazeb (mAbs) and Ervebo, respectively. In addition, several anti-EBOV treatments have been used experimentally in patients. One of the most important is Zmapp based on monoclonal antibodies (mAbs). However, the development and production of monoclonal antibodies for clinical use exhibits serious bottlenecks associated mainly with cost and scalability and is clearly amenable of improvement. The Zika virus has been responsible for 223,477 infection cases around the world from 2015 to 2018: Only in Mexico, 11,805 infection cases were reported in that time period. At this moment there are no FDA-approved vaccines for the Zika virus or specific treatment. The severe acute respiratory syndrome coronavirus type two (SARS-CoV-2) is the causal agent of Coronavirus disease 2019 (COVID-19) and, it has infected more than 50 million people, causing the death of more than 1.2 million people in less than 1 year. The fatality rate of this virus has been highly variable depending on the country. In Mexico, the fatality rate associated with COVID-19 (10%) is one of the highest in the world. Currently, no approved treatment for COVID-19 has demonstrated high effectiveness. Several vaccine candidates have entered the third phase of clinical trials but non-of them has not been yet approved. In addition to their high negative impact to public health, epidemic viral diseases have severely affected the economy and the dynamics of human societies around the globe. Moreover, the frequency of epidemiological emergencies associated to viral infectious diseases appears to have increased in the last two decades: SARS-CoV in 2002-2004, MERS in 2015, Influenza A/H1N1/2009, EBOV 2014-2016, Zika (2016) and COVID-19. In a world that is more and more connected, containing an epidemic episode is no minor challenge. Also, as COVID-19 has crudely demonstrated, our technological platforms to face pandemic diseases are still severely limited. Our capacities for fast development and deployment of diagnostic and therapeutic solutions were severely question this last year; COVID-19 showed that we need to do much better next time. In the front of diagnostics, available tools are currently centered in methodologies based on RT-qPCR. RT-qPCR exhibits unquestionable accuracy, but sadly depends on centralized facilities and highly trained personnel, which limits its scalability. We urgently need to make diagnosis accessible to all people, regardless of the geographic region, economy, and other factors that currently limit a timely diagnosis. In this thesis project, we describe the development of simple, cost-effective, and portable diagnostic techniques. Laboratories with expensive equipment are not required for the implementation of these techniques. In addition, the cost for implementation of these simple methodologies is up to 10 times lower than that associated with current qPCR-based techniques (techniques established as the “gold standard” by the health authorities for the diagnosis of COVID-19 or Ebola virus disease, for example). The development of therapeutic alternatives for the treatment of epidemic diseases is another front in which we experience severe limitations of fast response and scalability. For instance, one year after the onset of COVID-19, we are still unable to find a specific treatment for COVID-19. After many billions of dollars of investment, a reliable therapy for COVID-19 remains elusive. As for the case of Ebola treatment, monoclonal antibodies appear to be the most promising candidates for an effective treatment against COVID-19. However, the process of development of monoclonal antibodies for therapeutic applications is challenging. In part, this is due to limitations in the speed and robustness of the process of development of clones capable of produce relevant amounts of new biopharmaceutical compounds. Here, we describe the integration of different methodologies related to cell transfection and clone selection that may enable significant savings in term of time and resources to develop recombinant mAbs (in particular for EBOV), in shorter times.

Ciencias Exactas y Ciencias de la Salud

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