• We do not know whether hyperimmune immunoglobulin (a preparation made with antibodies from people who have recovered from COVID-19) reduces deaths or serious unwanted effects in people with moderate to severe COVID-19. But a similar preparation made by injecting animals with certain antibodies may reduce deaths, and serious unwanted effects and may stop people’s condition getting worse.
• We found no studies that investigated people with COVID-19 but without symptoms or people with mild COVID-19, so we do not know how effective human or animal hyperimmune immunoglobulin is for them.
• We found 10 ongoing studies. We will update this review when their results become available.
What is hyperimmune immunoglobulin?
The body produces antibodies as one of its defences against infection. Antibodies, or 'immunoglobulins', are found in blood plasma. They act as a critical part of the immune response.
Plasma from people who have recovered from COVID-19 contains COVID-19 antibodies, and can be used to make two preparations. Firstly, it can be used to make convalescent plasma, which is plasma that contains these antibodies. Secondly, it can be used to make hyperimmune immunoglobulin, which is more concentrated, and therefore contains more antibodies. The manufacturing process of hyperimmune immunoglobulin is complex and requires large pools of human plasma.
Similar antibodies can be made from animal sources and used in humans.
Why is hyperimmune immunoglobulin a possible treatment for COVID-19?
Hyperimmune immunoglobulin products contain high levels of antibodies that target SARS-CoV-2, the virus that causes COVID-19. The products are thought to inactivate the virus particles.
What did we want to find out?
We wanted to know if hyperimmune immunoglobulin is an effective and helpful treatment for people with suspected or confirmed COVID-19 in any setting (for example, home or hospital).
We were interested in:
• death from any cause up 30 days after treatment, 60 days, or longer if reported;
• improvement or worsening of symptoms;
• quality of life;
• unwanted effects.
What did we do?
We searched for studies that investigated hyperimmune immunoglobulin and usual care compared to usual care only, or in addition to a dummy medicine that did not contain any active ingredients (placebo).
To make a fair comparison, patients in the studies must all have had the same random chance (like the flip of a coin) to receive the hyperimmune immunoglobulin or the other treatment. The studies could include people of any age, sex, or ethnicity.
We compared and summarised the results of the studies. We used a standardised method to rate our confidence in the evidence. The confidence is based on study features such as how it was designed and the number of people in them.
What did we find?
We found five studies with 957 people. Studies took place in Pakistan, India, France, and Argentina, and one study was conducted in multiple countries, including Denmark, Greece, Japan, Nigeria, Spain, the UK and the USA. The studies took place before or during the emergence of several new COVID-19 variants and prior to widespread vaccine rollout. All the participants in four studies were unvaccinated. In one study, 12 from 579 participants were vaccinated.
We also found 10 ongoing studies.
All studies compared hyperimmune immunoglobulin from human or animal sources with usual care or placebo. The studies included only hospitalised people with moderate to severe disease. No studies looked at people without COVID-19 symptoms or mild COVID-19. No studies reported on quality of life.
We are uncertain whether or not hyperimmune immunoglobulin prepared from humans affects risk of death from any cause up to 28 days after treatment. It may have little to no impact on improvement or worsening of symptoms up to 28 days after treatment. We are uncertain about a possible difference in unwanted or serious unwanted effects. The individual studies decided which events to classify as serious unwanted effects, but this usually means something that may cause hospitalisation or permanent harm.
Hyperimmune immunoglobulin from animals may reduce deaths up to 28 days after treatment, may reduce worsening of symptoms, may improve patients' condition and may reduce serious unwanted events.
What are the limitations of the evidence?
We are uncertain whether hyperimmune immunoglobulin is an effective treatment for people hospitalised with COVID-19, and whether it affects the number of unwanted or serious unwanted effects because the studies were small and did not all provide evidence on all our points of interest. The studies were conducted predominantly in people from wealthy countries, before the widespread rollout of COVID-19 vaccines and the emergence of the omicron variant, so the results may not apply to people with omicron variant infection, or people who were vaccinated before falling ill.
There was no evidence for people without symptoms or with mild COVID-19.
How up to date is this evidence?
Our evidence is up-to-date to 31st March 2022.
We included data from five RCTs that evaluated hIVIG compared to standard therapy, with participants with moderate-to-severe disease. As the studies evaluated different preparations (from humans or from various animals) and doses, we could not pool them. hIVIG prepared from humans may have little to no impact on mortality, and clinical improvement and worsening. hIVIG may increase grade 3-4 adverse events. Studies did not evaluate quality of life. RBD-specific polyclonal F(ab´)2 fragments of equine antibodies may reduce mortality and serious adverse events, and may reduce clinical worsening. However, the studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern and prior to widespread vaccine rollout.
As no studies evaluated hIVIG for participants with asymptomatic infection or mild disease, benefits for these individuals remains uncertain.
This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence.
Hyperimmune immunoglobulin (hIVIG) contains polyclonal antibodies, which can be prepared from large amounts of pooled convalescent plasma or prepared from animal sources through immunisation. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID‐19). This review was previously part of a parent review addressing convalescent plasma and hIVIG for people with COVID-19 and was split to address hIVIG and convalescent plasma separately.
To assess the benefits and harms of hIVIG therapy for the treatment of people with COVID-19, and to maintain the currency of the evidence using a living systematic review approach.
To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Research Database, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform and Medline and Embase from 1 January 2019 onwards. We carried out searches on 31 March 2022.
We included randomised controlled trials (RCTs) that evaluated hIVIG for COVID-19, irrespective of disease severity, age, gender or ethnicity.
We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies that evaluated standard immunoglobulin.
We followed standard Cochrane methodology.
To assess bias in included studies, we used RoB 2. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), quality of life, adverse events, and serious adverse events.
We included five RCTs with 947 participants, of whom 688 received hIVIG prepared from humans, 18 received heterologous swine glyco-humanised polyclonal antibody, and 241 received equine-derived processed and purified F(ab’)2 fragments. All participants were hospitalised with moderate-to-severe disease, most participants were not vaccinated (only 12 participants were vaccinated). The studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern.
There are no data for people with COVID-19 with no symptoms (asymptomatic) or people with mild COVID-19. We identified a further 10 ongoing studies evaluating hIVIG.
Benefits of hIVIG prepared from humans
We included data on one RCT (579 participants) that assessed the benefits and harms of hIVIG 0.4 g/kg compared to saline placebo. hIVIG may have little to no impact on all-cause mortality at 28 days (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.43 to 1.44; absolute effect 77 per 1000 with placebo versus 61 per 1000 (33 to 111) with hIVIG; low-certainty evidence). The evidence is very uncertain about the effect on worsening of clinical status at day 7 (RR 0.85, 95% CI 0.58 to 1.23; very low-certainty evidence). It probably has little to no impact on improvement of clinical status on day 28 (RR 1.02, 95% CI 0.97 to 1.08; moderate-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if hIVIG has any impact on quality of life.
Harms of hIVIG prepared from humans
hIVIG may have little to no impact on adverse events at any grade on day 1 (RR 0.98, 95% CI 0.81 to 1.18; 431 per 1000; 1 study 579 participants; low-certainty evidence). Patients receiving hIVIG probably experience more adverse events at grade 3-4 severity than patients who receive placebo (RR 4.09, 95% CI 1.39 to 12.01; moderate-certainty evidence). hIVIG may have little to no impact on the composite outcome of serious adverse events or death up to day 28 (RR 0.72, 95% CI 0.45 to 1.14; moderate-certainty evidence).
We also identified additional results on the benefits and harms of other dose ranges of hIVIG, not included in the summary of findings table, but summarised in additional tables.
Benefits of animal-derived polyclonal antibodies
We included data on one RCT (241 participants) to assess the benefits and harms of receptor-binding domain-specific polyclonal F(ab´)2 fragments of equine antibodies (EpAbs) compared to saline placebo. EpAbs may reduce all-cause mortality at 28 days (RR 0.60, 95% CI 0.26 to 1.37; absolute effect 114 per 1000 with placebo versus 68 per 1000 (30 to 156) ; low-certainty evidence). EpAbs may reduce worsening of clinical status up to day 28 (RR 0.67, 95% CI 0.38 to 1.18; absolute effect 203 per 1000 with placebo versus 136 per 1000 (77 to 240); low-certainty evidence). It may have some effect on improvement of clinical status on day 28 (RR 1.06, 95% CI 0.96 to 1.17; low-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if EpAbs have any impact on quality of life.
Harms of animal-derived polyclonal antibodies
EpAbs may have little to no impact on the number of adverse events at any grade up to 28 days (RR 0.99, 95% CI 0.74 to 1.31; low-certainty evidence). Adverse events at grade 3-4 severity were not reported. Individuals receiving EpAbs may experience fewer serious adverse events than patients receiving placebo (RR 0.67, 95% CI 0.38 to 1.19; low-certainty evidence).
We also identified additional results on the benefits and harms of other animal-derived polyclonal antibody doses, not included in the summary of findings table, but summarised in additional tables.