Category: Disease/Health Area

With the world’s attention focused on SARS-CoV-2 and the serious impact COVID-19 is having both on our health and on society as a whole, it is worth noting that humans have in fact co-existed with numerous coronaviruses (CoVs) for millions of years. It is little understood how these related viruses have such startlingly different effects on infected individuals but some researchers have found evidence that mild CoV infection offers some protection from SARS-CoV-2. Could it be that the common cold may actually be a useful ally in our struggle to combat COVID-19?

It is only in recent years, after the emergence of SARS-CoV, that coronaviruses have been considered a significant threat to human health; before this time it was thought coronaviruses caused only mild respiratory infections in humans. HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1 are all endemic in the human population^1,2,3,4, causing 15-30% of respiratory tract infections each year and are mostly experienced as a mild cold by those infected. Only rarely do they lead to lower respiratory tract infections in high-risk individuals. This is in marked contrast to SARS-CoV, MERS-CoV and of course the current headliner SARS-CoV-2.

There is a clear distinction between the endemic, mild disease-causing Human CoVs and the three newly emerged, highly debilitating CoVs. With the latter all due to recent jumps from animal hosts it is clear that zoonotic diseases can be highly debilitating to the human immune system. However, with some individuals being exposed to the novel zoonotic CoVs and only eliciting mild symptoms, is there any chance that the endemic, older strains may be serving up some protection that explains this variability in disease progression?

Tantalisingly, this has been suggested by a recent study published in Science by Jose Mateus and colleagues⁵. Using samples from unexposed individuals the team were able to identify memory CD4+ T cells that cross-reacted with the four common cold coronaviruses and to SARS-CoV-2, suggesting that previous infection with a milder coronavirus may produce CD4+T cells that can also protect against COVID-19. In accordance with this finding it was also recently found that children that had developed a serious form of COVID-19, called multisystem inflammatory syndrome (MIS-C) carried no antibodies to two of the common endemic coronaviruses, unlike children who had suffered only mild COVID-19 symptoms⁶. The authors speculated that this lack of protection may have played a role in the serious disease progression seen in these small number of cases.

Another interesting study analysed the CoV-specific antibody repertoires in children and adults and found these to be qualitatively different between these two groups. The anti-HCoV IgG specificities in children were more likely to target regions that are functionally important and structurally conserved in the viral spike and nucleocapsid with some appearing to be broadly cross-reactive across human CoVs⁷. This fascinating insight into differences in the immune response between adults and children could in part explain why COVID-19 disease is much milder in younger members of the population as well as hinting at the possibility of cross-reactivity of antibodies generated to previous mild CoV infection.

Although highly speculative at the moment, the cross-reactivity of antibodies generated to mild endemic CoVs may in part explain the huge variance in COVID-19 disease states. Perhaps in a COVID-19 future we will embrace catching a common cold each year, celebrating the antibodies it has gifted us to protect against its more dangerous relatives.

Antibodies that cross-react between coronavirus strains may be highly desirable in the population but for in vitro diagnostic SARS-CoV-2 antibody tests it is essential that such tests do not detect antibodies individuals have raised against the other endemic CoVs. The FDA publishes a list of potentially cross-reacting markers that manufacturers of SARS-CoV-2 antibody tests wishing to gain Emergency Use Authorisation should ensure are not recognised by their test. These include antibodies to the 4 circulating human CoVs as well as antibodies raised against various other infectious diseases.

Patient/donor serum and plasma specimens collected before the COVID-19 pandemic and containing measured levels of these potential cross-reactors are available at Logical Biological.

The current US FDA list (as of 23^rd September 2020) is:

Human Immunodeficiency Virus (HIV) has a reputation for being difficult to treat, although advances in medicine have reached a level where those being treated can be expected to live almost to their full life span. However, as we shall see in this article, current HIV testing is not perfect and many challenges remain.

There are multiple HIV viruses

HIV is actually a small family of distinct viruses comprised of HIV1 and HIV2. HIV1 accounts for 95% of worldwide HIV infections, while HIV2 is largely concentrated in West Africa. The two viruses are genetically related yet clearly distinct; HIV2 is less infectious than HIV1 and progresses more slowly. The two viruses also respond differently to some drug therapies; for example, HIV2 is less responsive than HIV1 to enfuvirtide and non-nucleoside reverse-transcriptase inhibitors. Nevertheless, it is essential that any medical diagnostic test can detect both viruses.

Further complicating matters, within HIV1 there are many different, i.e. genetically distinct, virus subtypes, some of which are extremely rare. How can HIV disease diagnosis test manufacturer ensure their test detect HIV1 subtype N when only a handful of such infections have ever been recorded? Clearly, the patient material needed to check that subtype N is detected cannot be readily available.

Diagnosing newly-infected patients

One convenient and successful way of diagnosing HIV antibodies is to look for evidence of an immune response in the patient, i.e. does the patient’s blood contain antibodies raised against HIV? Human IgM and IgG anti-HIV antibodies can be readily detected using HIV antigens, typically in the form of synthesised peptides or recombinant proteins. But what if the patient has only just become infected and has not yet developed an immune response to the virus?

If such patients are only tested for antibodies to HIV they could receive a negative test result and then unknowingly go on to infect other individuals. It would be ideal to be able to effectively diagnose newly infected patients and this is why HIV p24 antigen tests are used. p24 is an abundant protein within HIV, making up most of the viral core. Unfortunately, although p24 is detectable earlier than the patient’s antibody response, p24 is not immediately present at detectable levels in the patient; there is still a “window” of time where a newly infected individual will test negative.

Different patients, different responses

Each type of HIV test has a known post-infection time window during which it cannot be expected to detect HIV in patients. However, there is a strong intra-patient variation when each test becomes positive. As an example, Hurt et al. (2017)1 noted that 4th generation tests (inclusive of p24 testing) are positive for 50% of infected individuals at day 17.8, 75% at day 23.6 and 99% at day 44.3. This is why it is so important to test each patient for a battery of different viral and host components, as in 4th generation testing, as some components may be absent in a given patient.

Access to Patient Material

The disease diagnosis community needs ready access to HIV patient material for use in assay development, assay calibration and quality control of HIV tests. Different strains, subtypes, ages, genders and stages of infection may be required. Companies such as Logical Biological specialise in this area, working directly with donor collection centres.

Niche scenarios

Babies carry their mother’s antibodies for the first months of their lives so tests to detect antibodies in the babies blood would be expected to be positive even if the baby is not infected. In this not so unusual scenario of a baby being born to a HIV-infected mother, as well as a few others, a test for Viral Load may be beneficial. Viral load tests for HIV use Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) to amplify HIV RNA if present in the blood. These tests are complex and expensive to perform, and no tests of this type have been approved for diagnostic use by the FDA.

Presence of HIV in donated blood

Donated blood products could be infectious, as some donators are not aware that they are infected. While individuals at high-risk of infection are discouraged from donating, clearly there is a risk of infection being spread through donated blood and this is mitigated by testing all such blood for a number of different infectious diseases. The National Health Service in the UK tests all donated blood for Syphilis, Hepatitis B (HBV), Hepatitis C (HCV), Hepatitis E (HEV), Human T Lymphotrophic Virus and (HTLV)5.

Some other infections are tested for in addition depending on the donator’s individual circumstances. Donated blood is typically tested using the RT-PCR method. Worryingly perhaps, this test is also not perfect; the risk of spreading infection through donated blood cannot be eliminated entirely. Patients won’t be positive for the HIV viral load test until a few days post-infection, and the time-window is even a few days longer where patient material is pooled, and thus diluted.

Self-testing & In-Field Testing

Not every unknowingly infected HIV patient would be willing to go to a clinic to get tested, even if they understand they are at high-risk and fear they might be infected. Partially addressing this problem, a market has developed around self-testing of HIV at home, and it is now straightforward to buy such tests from any self-respecting online retail giant.

Alternatively, imagine a remote rural location in a country with limited healthcare infrastructure – individuals might not be able to get to a clinic even if they wanted to. It is up to governments, regulators and assay developers to adapt to this need and by doing so they will improve the protection of the public and make a contribution to alleviating the HIV epidemic. It is noted that in one of the worse affected countries – South Africa – 90% of people living with HIV are now aware of their status, up from 66% in 20146; progress is being made.

Conclusions

The disease diagnosis community has made great strides in improving HIV detection. However, many challenges remain owing to the biology of the virus and its human hosts, human behaviour and the individual circumstances of those infected. Future trends are likely to see an increase in home/self-testing and movement towards 5th generation assays which give individual results for HIV1, HIV2 and p24 in the initial test providing valuable information to determine the most appropriate treatment for the particular individual.

References:

1. Selecting an HIV Test: A Narrative Review for Clinicians and Researchers. Hurt CB, Nelson JAE, Hightow-Weidman LB, Miller WC. Sex Transm Dis. 2017 Dec;44(12):739-746.
2. Human anti-HIV IgM detection by the OraQuick ADVANCE® Rapid HIV 1/2 Antibody Test. Guillon
   G, Yearwood G, Snipes C, Boschi D, Reed MR. PeerJ. 2018 Feb 28;6
3. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, Peddada L, Heldebrant C, Smith R, Conrad A, Kleinman SH, Busch MP. AIDS. 2003 Sep 5;17(13):1871-9.
4. Assessment of the Ability of a Fourth-Generation Immunoassay for Human Immunodeficiency Virus (HIV) Antibody and p24 Antigen to Detect both Acute and Recent HIV Infections in a High-Risk Setting. J Clin Microbiol. 2009 Aug; 47(8): 2639–2642. Mark W. Pandori, John Hackett, Jr., Brian Louie, Ana Vallari, Teri Dowling, Sally Liska, Jeffrey D. Klausner.
5. https://www.blood.co.uk/the-donation-process/further-information/tests-we-carry-out/
6. https://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/south-africa
7. https://www.avert.org/professionals/hiv-science/types-strains