OPINION | Technological advances helping in the fight against emerging infections

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Within a few weeks after SARS Coronavirus 2 (SARS-CoV-2), the virus causing Covid-19, was discovered, scientists characterised its full genome, meaning that they obtained all its genetic information.

They managed to pull this off in such a short period thanks to rapid developments in the science of nucleic acid (information-carrying molecules in cells) sequencing in recent years.

Knowledge of the genetic sequence of this novel virus enabled scientists to develop diagnostic methods that were used to trace the epidemic, and allowed them to start the process of vaccine development.

It’s important to keep in mind that each disease-causing agent or pathogen has a unique genetic code. Deciphering this code is very important in the fight against new infectious agents. Similar to a string made with four colours of beads, genetic codes are a sequence of four different building blocks that are bound together. 

Genetic codes have two main forms: the permanent genetic code of living organisms is deoxyribonucleic acid or DNA, whereas ribonucleic acid or RNA, specifically messenger RNA or mRNA, is a short-lived code required by the protein factories of cells to determine the sequence of amino acids, which when tied together, make up peptides or proteins.

The first pathogens to be discovered and characterised were bacteria which could be cultured in laboratories using liquid broths or culture plates. Similarly, yeasts could be grown in suitable laboratory culture media.

However, not all infections can be diagnosed this way as not all infectious agents grow in these media. Therefore, modern diagnostic tests rely a lot on detecting genetic codes.

Different techniques developed

Viruses consist of a genetic code, which for different kinds of viruses is either DNA or RNA. This DNA or RNA is packaged in a protein shell and some viruses also have a membrane.  As viruses do not have their own protein producing factories, they are completely reliant on living host cells to produce offspring.  

The first human viruses were identified by growing them in living animal cells or laboratory animals, but many viruses do not grow in these laboratory systems. Therefore genetic-code-based diagnostic methods, called molecular diagnostic methods, have revolutionised diagnostics and enabled the detection of new viruses and other organisms that are difficult to grow in laboratories.

These methods use the same system that copies DNA or RNA in living cells. The best known is the polymerase chain reaction (PCR) that was invented by Kary Mullis in 1983 and which uses the enzyme that replicates DNA to make billions of copies of DNA from a single molecule.

Different techniques have also been developed to decipher the sequence of DNA or RNA building blocks, referred to as nucleic acid sequencing. Recent developments made these methods a lot faster, which was elegantly exploited in characterising the genetic code of SARS-CoV-2.

Once the sequence of SARS-CoV-2 had been known, PCR-based diagnostics were developed which allowed the rapid diagnosis of Covid-19 on respiratory samples.

A few years ago, PCR diagnosis was restricted to research laboratories, but in response to other pathogens such as HIV, hepatitis C virus, and mycobacterium tuberculosis (MTB), the bacterium that causes Tuberculosis, commercial automated tests became widely available.

Some of these are large, automated instruments, ideal for large high throughput laboratories that often process thousands of samples in a day and that are often found in cities close to large hospitals, while small footprint platforms that do not take up much space or need much electricity enable fast diagnosis at the point of care (PoC).

These are suitable for peripheral clinics that see a few patients a day. Multi-use small footprint platforms for PoC diagnosis have become essential in MTB diagnosis and the diagnosis of HIV in infants born to HIV-positive mothers. More recently, laboratory test reagent kits have also been developed for PoC platforms to diagnose the Ebola virus and SARS-CoV-2.

With technological improvement, PCR diagnosis has become invaluable in the response to these emerging pathogens. Progress in alternative methods that use antibodies to detect antigens (structures that antibodies recognise) from infectious agents has offered rapid tests, ideal for PoC and much cheaper than PCR-assays.

Unfortunately, these cheaper rapid methods do not perform as well as PCR when there is little infectious material. PCR tests, albeit more expensive, are therefore often more accurate.

Rapid development crucial

Previously, vaccines were made by inactivating (killing) living organisms, referred to as inactivated vaccines or by growing them in cell culture, until they spontaneously mutate to become safer or attenuated, called live attenuated vaccines.

Inactivated vaccines, however, often do not elicit a strong and protective immune response, whereas live attenuated vaccines take long to make and have safety concerns as they might back-mutate to become pathogenic. 

Recently, different approaches have been followed: carrier viruses, called vectors that do not cause disease, were used as a backbone to insert a code for an ebolavirus protein, to successfully vaccinate people against ebolavirus disease. Using the same backbone but inserting the spike protein (the most important surface protein) gene of SARS-CoV-2 provided a vector-based vaccine produced by Johnson & Johnson.

A similar vector-vaccine approach was followed for the Oxford-AstraZeneca vaccine. An even more direct and elegant method is to deliver the genetic code for protein production to living cells, using mRNA vaccines.

As mRNA is very short-lived when unprotected and difficult to get inside cells, the major challenge was to develop a packaging system to deliver mRNA inside living cells, where the virus specific proteins would be produced.

These technologies were first developed for cancer, but offered an exciting new approach for infectious disease vaccination, as the process to make mRNA is a lot more direct and scalable than older vaccine approaches.

Such rapid vaccine development is crucial when fighting a new global pandemic. Clinical studies have since showed that these mRNA vaccines for Covid-19 made by Moderna and Pfizer-BioNTech were safe and very effective against Covid-19.

The recent progress in diagnostics and vaccine development will remain essential in the fight against current and future emerging infectious diseases. The novel technologies used in the characterisation of SARS-CoV-2 would remain important to detect new pathogens.

Also, mRNA and vector vaccine technology used in the rapid development of vaccines against Covid-19 will remain key in responding to current important infections for which no effective vaccine is, as of yet, available and to respond fast to future pandemic threats.

*Prof Gert Uves van Zyl is a pathologist at the National Health Laboratory Service, Tygerberg business unit, and professor in the Division of Medical Virology at Stellenbosch University. This article is based on his recent paper “New Technological Developments in Identification and Monitoring of New and Emerging Infections” in Reference Module in Biomedical Sciences (2021).

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