"The clinical trial that we are participating in partnership with the NIH/NIAID to evaluate our hyperimmune globulin (H-Ig) is unrelated to, and is unaffected by the FDA decision regarding emergency use authorization for COVID-19 convalescent plasma for transfusion.

Our trial is a global multi-centre, double-blind, placebo-controlled, randomized study and is adequately powered to show whether the H-Ig treatment is safe and effective against COVID-19.

We have had discussions in advance with both the FDA and EMA to ensure the trial design meets their requirements.  Additionally, as the H-Ig is a standardized and more concentrated amount of convalescent antibodies, we are hopeful this would translate into an even stronger efficacy signal."

Background on CSL’s COVID-19 Plasma Projects (not for direct attribution to Dr Nash):

CSL is one of the founding members of the COVID-19 Plasma Alliance to develop a potential plasma-derived hyperimmune therapy for the treatment of serious complications from COVID-19 in the US and Europe. We expect patients in the Northern Hemisphere Phase 3 trial to begin this month.

We are working on a similar plasma product for the Australian market to treat people with serious complications of COVID-19, to be known as COVID-19 Immunoglobulin and this is currently under development at Broadmeadows. In support of this program, 500 donors have generously provided their plasma through our partnership with the Australian Red Cross, to support the first batch of product for a clinical trial of that medicine.

It is important to note the difference between Convalescent plasma for transfusion and convalescent plasma used in the manufacture of a Hyperimmune Globulin (H-Ig). The FDA decision refers to plasma that has been collected from recovered patients and transfused directly to people experiencing serious complications from COVID-19. CSL Behring is developing a H-Ig therapy derived from convalescent plasma that has been pooled, processed and purified to concentrate antibodies. The table in this article by CSL Behring explains the difference.

Convalescent plasma, and related blood products, are obtained by collecting plasma from patients who have survived a previous infection and developed antibodies to an infectious agent. Antibodies are produced as part of our humoral immune response to infectious diseases. In the specific case of viruses like SARS-CoV-2, antibodies produced by our bodies can bind to the surface of the virus and stop it in its tracks ("neutralise").

The concept of using convalescent plasma to treat infectious diseases is not new. The first best documented case was for the Spanish influenza pandemic, where convalescent plasma was used as a potential therapy with mixed results. It has been used in a variety of recent cases, including Ebola, SARS CoV1 and MERS.

For COVID-19, convalescent plasma is being used as either one or a small number of donors pooled for treatment. In contrast, CSL and other global companies as part of the Alliance network are  pooling product from many donors and concentrating it. This is referred to as hyper-immune IgG product.

Many studies are now looking at this for COVID-19. Many small studies have had mixed results, but what is required are larger studies with more people. Key to success will be the potency of the plasma from each recovered patient. Not everyone has the same potency and studies at the Kirby Institute at UNSW are helping efforts by working with LifeBlood to highlight which donors may be suitable for donating of plasma for these efforts. From this data, LifeBlood can work with companies such as CSL to make plasma products for use in clinical trials.

Before treatments are administered to patients there should be convincing evidence of both effectiveness and safety. Convalescent plasma is an exciting possible treatment for COVID-19. At this time, there is good evidence of safety. However, proof of effectiveness can come only from well-designed randomised controlled trials in which patients given the treatment are compared with patients who could have received the treatment but didn’t receive it. Such trials have commenced but have not yet been completed. Until such trials are completed and reported, the effectiveness of convalescent plasma remains uncertain.

Today, the Food and Drug Administration has announced the emergency authorisation of convalescent plasma to treat COVID-19 patients, on the basis it reduces 35 per cent of mortality. While the option of administrating the plasma of COVID-19 patients that have recovered from infection and contain antibodies to neutralise the virus seems attractive, this emergency authorisation is, unfortunately, not based on proven scientific grounds and is even dangerous. Only one large observational study has been published and shows an incremental improvement, and randomised clinical trials showed no efficacy of convalescent plasma treatment for COVID-19. Overall, it shows there are no silver bullet treatments for COVID-19 and, to-date, preventive measures such as wearing masks, maintaining social distancing or staying at home are the most successful for COVID-19.

We really have to tread gently with announcements such as this, about potential treatments for COVID-19. There has been so much speculation, and quite rightly, about when a treatment or vaccine may be available and when life can return to normal. However, the impacts of COVID-19 on mental health and wellbeing have been, and continue to be, severe around the world, with increases in depression and anxiety, social isolation and ageism. We must be careful not to make premature announcements, especially if motivated by garnering public support, and information needs to be shared judiciously and with reverence to the level of evidence supporting such announcements. We need to respect the current heightened emotional state of people, especially those living with chronic illnesses that place them more at risk of poor outcomes from COVID-19. Whilst hope is a good thing, hopes pinned on treatments with little or no evidence can be a further threat to population wellbeing.

The use of convalescent plasma (which contains antibodies) has been used for over 100 years, including during the 1918 Spanish influenza pandemic. The principle is that recovered patients have antibodies in their blood, which can be used to treat people who are acutely ill.

Non-specific immunoglobulins (antibodies) have been used successfully against hepatitis A, and disease-specific immunoglobulins from convalescent patients have been used for many diseases including varicella-zoster (chickenpox, shingles) and smallpox.

The controversy over the use of convalescent plasma for COVID-19 has arisen about using it without robust randomised controlled trial data. Preliminary data from the Mayo Clinic, and also from other sites, suggest it is effective. In the Netherlands, it did not seem that convalescent plasma made much difference, but in that case it may have been given too late. A US study showed it needs to be given early to be effective. The question is whether therapies can be provided under emergency authorisation while awaiting larger studies. Other treatments such as Remdesivir have been used in this way, so it is reasonable to offer convalescent plasma in the same way.

This is a sensible move to help treat patients with COVID-19, and is already being done in Australia as part of the clinical trials AustralaSian COVID-19 Trial (ASCOT), and the Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP). These clinical trials will provide the evidence needed to say if convalescent plasma (plasma from someone who has recovered from COVID-19) is a safe and effective treatment option. Whilst there is not a lot of data around how effective this approach may be, initial studies on small numbers of patients have shown promising results.

Plasma collected from patients two to four weeks after they have recovered from a viral infection frequently contain high levels of neutralising antibodies. Administration of convalescent plasma to patients with life-threatening viral infections has a long history and was shown to be of some clinical benefit as long ago as the Spanish influenza pandemic and as recently as SARS and MERS.

During the current pandemic, convalescent plasma has been used as an additional tool with which to treat patients with severe infections and appears to have some benefit. A recent US-based multicentre study of 189 patients hospitalised with severe COVID-19 infections, of whom 115 were treated with convalescent plasma, showed shorter hospital stays and reduced mortality in the treated group.

While a major effort is being made to increase the supply of convalescent plasma, quite a lot of people who recover from COVID-19 have underlying health issues or are disqualified from being donors for other reasons.

There are many unanswered questions about the SARS-Cov-2 virus on how it works, why it presents in so many varied ways, why some are unaffected and some die, and whether or not immunity is conferred by infection.

Any attempt to rush through a treatment solution, whether it is a drug, a vaccine, or a convalescent plasma transfusion is fraught with uncertainty and possible dangers. Although thousands of plasma transfusions have been tried out in the USA and some in China, the current evidence indicates that these procedures may only be effective in some patients and a definitive study with appropriate controls has yet to be carried out. The virus itself causes variable seroconversion (antibody formation) in infected patients and the antibodies do not appear to be particularly stable - though it is still too early to be certain. That means selection of recovered patients for obtaining blood plasma to transfuse will be hit or miss and difficult to standardise. The procedure is to mix together plasma from multiple recovered patients to avoid this, but it has not been exhaustively studied.

Current evidence indicates that innate or acquired cell-mediated immunity to the virus is an important part of the overall protection process against the SARS-COV-2 virus. The immune system works both by cellular and humoral processes (the latter by antibodies etc. carried in plasma). Plasma is, by definition, cell-free, so a major component of the active protection mechanism - the cell-mediated response (which is still poorly understood in COVID-19) - is missing completely, which will inevitably limit the efficacy of plasma transfusions.

Convalescent plasma transfusion is absolutely not a practical pathway to population protection - there are too many scaling issues. However, it may still have value for treating critically-ill patients at the local level and, as a treatment of last resort, should never be denied if available. In less critical patients, there would be multiple safety and efficacy concerns and practical issues even for this limited use and these have not been addressed systematically. Because this therapy misses the cell-mediated immunity pathway to treatment that might be the most critical in fighting off the disease, the effectiveness of the therapy is questionable at large scale and results might be very patchy. It is certainly not going to be a magic bullet or a wonder cure that the White House craves for, and the rapidly introduced order once again is driven by politics rather than strong science, and that, so far, has been a public health disaster for the USA.

This is interesting, but a long way from being safe to trial in patients, let alone treat patients outside of a clinical trial. The immunological information to date is suggestive enough that more research is needed to understand the complexity and variability of the production of such immunological response in different donors, and the expected wide variability of response in each patient.

Once we understand that, we probably need a lot of pharmacological and toxicological work-up on dose, timing, repeat treatment, and individualising the dose based on the response of the patient - a very long way from readiness for patients. It would be better if we could invest the funds in getting the research done first, so we don’t get negative clinical outcomes just because we didn’t understand how to use it, rather than that it doesn’t work.

Convalescent plasma is a promising therapy for COVID-19, but should still be considered experimental. Despite the recent announcement by President Trump, there has not been clear evidence from randomised controlled trials demonstrating a clinical benefit of convalescent plasma compared to the best standard of care. In Australia, there are two clinical trials testing convalescent plasma. ASCOT is for hospitalised patients who are not on a ventilator, and REMAP-CAP is for patients in intensive care units. In these trials, patients will be randomly assigned to the best standard of care or the best standard of care plus convalescent plasma. The convalescent plasma is being provided by Australian Red Cross Lifeblood.

Convalescent plasma is basically collecting plasma from people who have already been infected with SARS- COV-2 and have recovered (thus, they are in the convalescent of infection) and infusing this plasma into individuals. This could either be for prophylactic treatment of people who are likely to be exposed to SARS-COV-2 (eg. frontline health care workers, aged care residents and staff) or to treat people who have been recently infected.

This is a form of 'passive immunity'. It relies on the original individual generating antibodies against SARS-COV-2, when they were themselves infected, these antibodies can be found in that persons plasma and they function to neutralize the virus. So the plasma is collected, cleaned up a bit, tested to make sure these antibodies are present, and then concentrated and administered to other individuals.

In simple terms it is a bit like a blood transfusion, or using plasma fractions to treat people with hemophilia. That is taking something from healthy peoples' blood and using it to prevent/treat a disease that is occurring in someone else, because at that moment in time they are lacking the 'essential ingredient' themselves to stop the disease.

This is not a new concept – it has been used decades ago (nearly 100 yrs ago actually) to treat measles, polio and other infectious diseases in the early 1900s. it is also how anti-venom against snake bites is generated.

For COVID-19, there have been some studies showing that convalescent plasma is a safe treatment, but it is unclear whether it is effective for all patient. It probably depends on when the patients receive this treatment.