Issue #76: The monoclonal antibody story part 7: anti-viral applications

Written by Nobel Laureate Professor Peter Doherty

Way back at the beginning of the mAb story (#71), one of their first uses in infectious disease surveillance was to to identify novel influenza viruses. When mice were immunised with, say, the highly variable influenza hemagglutinin (HA) protein (#46) the next step was now (rather than taking blood to separate polyclonal immune serum) to ‘immortalise’ antibody producing B cells by making  hybridoma cell lines, each of which produced a single, monospecific IgG (#21). These very precise reagents could then be used to type HA-different (#19, #20) flu strains. My other (after Rolf Zinkernagel, #32) Swiss research collaborator, Walter Gerhard at The Wistar Institute, Philadelphia, was the first in that field, where he worked with the world’s leading avian influenza virologist and another close colleague, New Zealander Rob Webster, who started the WHO Collaborating Centre for Studying the Ecology of Influenza in Animals at St Jude Children’s Research Hospital, Memphis. The other five WHO Collaborating Centres for Influenza all focus on the disease in humans, with the Doherty Institute hosting the Melbourne branch led by Kanta Subbarao.

Distributing these mAb reagents across the planet meant that all diagnostic and research laboratories were now on the same page, and greatly enabled epidemiological analysis. Reflecting the rapid march of contemporary science, though the mAbs are still important for standardising neutralization and other Ig-based assays, they are now less prominent on the influenza surveillance front. Today, influenza virus isolates are rapidy characterised by gene sequencing, with particular reference to the viral HA that is subject to antibody-mediated selection and leads to the emergence of the new, seasonal influenza strains which require novel vaccines to be made on a yearly basis. The influenza viruses mutate at a much higher rate than the CoVs (#46, #64), and the question in everyone’s mind is whether we will need to be continually making new vaccines specific for SARS-CoV-2 variants. Through the COVID-19 pandemic, sequencing the genes encoding the spike protein of SARS-CoV-2 has facilitated the rise of genomic epidemiology, where virus variants ‘bar-coded’ by minor mutations can be used to  trace local chains of virus transmission.

The diagnostic and lab-reagent monoclonal technology described above was all pursued very satisfactorily with mouse mAbs but, when we started seriously down the road of making mAbs of human origin (#74), there was a further intriguing surprise. Investigators found, with top Italian immunologist Antonio Lanzevecchia being prominent in this field, that some very rare, influenza-specific mAbs could neutralise a whole spectrum of different influenza variants. That immediately raised the question: how might we ‘persuade’ the human immune system to preferentially make such cross-reactive antibodies and, in effect, produce  ‘universal’ influenza vaccines that would not need to be ‘rejigged’ from year to year? So far, we have not worked out how to do this, and there’s a further concern that some such mAbs may be too close to recognising ‘self’ (our own body proteins) and be autoreactive.

These highly cross reactive mAbs do, though, have their uses in clinical medicine. The Australian Government has purchased 7700 doses of Sotrovimab which, found years back while researching the immune response to the 2002/3 SARS-CoV-1, binds to neutralising spike protein determinants on all the human beta CoVS, including SARS-COV-2. As a consequence, it should work against any variant of SARS-CoV-2 spike, while some of the other, highly specific human mAbs used early on to treat people with COVID-19 will not neutralise mutated viruses that no longer express that particular spike protein antigen.  Furthermore, Sotrovimab is an ‘engineered’ form of the original mAb that has been modified to have a long half life – it takes 48 days to fall to half the injected levels in the blood. Providing we had enough doses, which we currently do not, Sotrovimab could be used to treat people infected with some future, highly virulent immune-escape variant (#64) of SARS-CoV-2 though, once we have small molecule drugs (#67) that are also broadly cross reactive, they would be a much cheaper alternative. As discussed previously, a possible candidate that is making its way trough trials is Molnupiravir (#66) which, unlike a mAb, can be taken as a pill and does not need to be injected. Where long-acting mAbs might be useful until a new vaccine against a novel and dangerous variant can be developed is to protect frontline healthcare workers, immigration personnel and the like.

At present, following President Trump’s promise of free availability (#74), the USA has given neutralising mAb treatment to something like 40,000 unvaccinated people who caught COVID-19 in Florida alone. We do not currently have this resource available to us in Australia. The only way, and indeed the sensible and cheap way, for a healthy Australian  to access protective SARS-CoV-2 specific antibodies is to follow ‘nature’s plan’ (with a bit of human help), get the two vaccine jabs, and be your own antibody production factory. Apart from anything else, your ‘self-tailored’ IgGs (#21) will be available from the moment you are infected, you don’t need to go to a doctor’s office to get a drug or an IV mAb infusion (if that was available), you will maintain high enough neutralising antibody levels in your  blood for at least 6-8 months after the second vaccine shot (not just for 48 days) and a third dose will further boost your immunity. Once you’ve ‘jump-started’ the antiviral immune reponse with a vaccine, it’s ‘natural immunity’ all the way!