Armed with antibody studies: On COVID-19 serosurveys

To tackle the COVID-19 pandemic it is essential to understand the exact transmission dynamics and statistics of the disease. While racing against time to develop a therapy and vaccine to fight this aggressive invader, scientists are trying to develop cheap and accurate serology tests for mass serosurveys.

Why is serology or serosurvey the ‘pandemic buzzword’?

Serology is broadly the scientific study of blood serum and other body fluids. In practice, it is the identification of antibodies in the blood. In the context of COVID-19 serology tests determine the presence of antibodies produced against SARS-CoV-2, the virus that causes COVID-19. When serology studies involve mass populations, they are called serosurveys or population seroprevalence studies. To understand why serosurveys are being widely planned and conducted, we need to first understand the antibody kinetics or antibody dynamics of a typical COVID-19 patient.

Based on latest studies, when SARS-CoV-2 invades the body, it incites cell-based and antibody-based immune responses. Analysis of antibody expression patterns in singular index cases and patient cohort studies reveals that IgM antibodies are produced in detectable quantities within 7 days (which in some acute infections can happen as early as 3 days). IgM keeps increasing in titer, until starting to wane slowly, and is nearly undetectable in 4 weeks’ time. In most cases, within two to three weeks of the initial infection, the body launches a secondary humoral immunity response by producing IgG antibodies.

A serosurvey detects the presence or absence of IgM and IgG antibodies, sometimes only IgG, in a sample population to determine the seropositive percentage and thus the past infections otherwise hidden in the population. An ideal seroprevalence study combines these results with knowledge of antibody dynamics and utilizes contact tracing data of the participants to perform statistical calculations to arrive at actual percentages of infections better informing the governments and public.

Incidentally, I was directly involved as a lab-testing volunteer in USA’s first mass seroprevalence study with 3330 participants led by Stanford Scientists in Santa Clara county of California. This study used a qualitative rapid strip-based test to determine the percentage of COVID-19 infected population of Santa Clara including past and asymptomatic ones. Participants’ blood samples were collected at multiple drive-through sites over two days in early April 2020. When volunteering for the yet unpublished Santa Clara study, I noticed that majority of the participants were driven by an eagerness to know their COVID-19 susceptibility versus immunity status, an idea that changed over time.

So far, COVID-19 serology tests aren’t at a stage where a singular test can provide accuracy, rapidity, economy, and simplicity all in one. Thus, determining individual infection or susceptibility status through mass serology testings is still a ‘work in progress’. However, despite the deluge of controversies, serology tests present a considerable advantage of tracing past (including asymptomatic) infections, unlike molecular diagnostic tests, which can only detect active cases.

Looking through the rearview mirror

Serology testings are like looking backwards through the ‘rearview mirror of a car’. In other words, serosurveys constitute a retrospective diagnostic and surveillance system to fight a rapidly progressing and evolving pandemic situation like COVID-19. A population seroprevalence study, when designed, implemented, and analyzed correctly, not only allows us to understand the number of past infections but also elaborates the rate of infectivity, infection fatality, and transmission dynamics.  A weekly IgG seroprevalence study in Geneva, Switzerland involving former Bus Sante survey participants and their household members including children can be considered a great example.

This team did some rigorous serosurvey on 2766 participants from 1339 households using ELISA for twelve consecutive weeks and reported the findings from five weeks in their June publication. According to their report, community infection percentage swayed between 4.8-10.9% over a period of 5 weeks, with children between 5-9 years and people above 65 years exhibiting relatively lower number of infections. For the aged subgroup it could arguably be the case that they either reflected an actual lower exposure, or higher fatality rate, or were indisposed to take part in surveys like this. But for children, the outcome seemed real, although different antibody kinetics could be an unlikely possibility. Nonetheless, this study estimated 11.6 undetected infections per reported case in the community, information that could have a bearing on reopening decisions.

Another published study applauded for improved study-design was a nationwide serosurvey in Spain, that recruited from households using municipal rolls. This study involving more than 60,000 participants, estimated IgG seroprevalence to be 4.6% by a chemiluminescent particle-based immunoassay and 5% by point-of -care test, with variations among regions and negligible seropositivity in children. Importantly, here too a third of the seropositive individuals were asymptomatic, not likely to be detected otherwise.

Among other published reports from around the world, one carried out in three rounds of probability sample household in the state of Rio Grande do Sul, Brazil, indicated seropositive percentages (ranging from 0.048-0.222%) with significant upward trend between first and third rounds. This investigation across nine large municipalities with more than 4000 participants and 37 family members of seropositive individuals found a 35.1% seropositivity among cohabitants, indicating a high rate of contact transmission.

In the US, two of the first county-based studies in California, with some overlapping investigators and the same questionable rapid lateral flow immunoassay indicated the presence of hidden infections in the population. While the published study from Los Angeles County that tested more than 850 individuals estimated the seropositive percentage to be 4.65%, the pre-publication release from Santa Clara county estimated a range between 2.5-4.2%. Several other serosurveys are either underway or have announced preliminary results, corroborating a similar estimation of high undetected seropositive population, but an absence of herd immunity (at least 60-70% seropositivity). An important serology study accepted for publication recently implied asymptomatic healthcare workers to be a likely source of community transmission. Out of the 249 personnel tested within the first month of caring in Nashville, Tennessee, 7.6% (19) were seropositive, among whom only 57.9% (11) were symptomatic.

Great expectations!

As a result of these serosurveys, two phrases that made the rounds (in April or even early May of 2020), ‘herd immunity’ and ‘immunity passport’, have been proven utopic in the context of COVID-19. Numerous serology studies carried out till now indicate that the human race has not developed any natural herd immunity to the SARS-CoV-2 virus. This means that we all do our best in prevention following basics like washing hands, wearing masks, and practicing social distancing.

Also, as reports constantly come in, it is unlikely that IgG and neutralizing antibodies against SARS-CoV-2 persist in blood beyond a few months. Thus, although that might impart some degree of protection to the one’s infected, it is not sufficient to issue the so-called immunity passport, putting reopening decisions to reassessment.

Serosurvey reports:  An upgraded weaponry for newer battles

As disappointing as these findings might seem, we can at no cost overlook the fact that these are products of rigorous serosurvey efforts and have important bearing on formulating current public policies and mass preventative strategies. Additionally, serosurvey results paint a better picture of the pandemic statistics and help researchers design more realistic epidemiological models.

With researchers, healthcare workers and decision makers understanding the importance of developing cheap and accurate serology testing tools and their mass-production, there is already a lot of cross-disciplinary collaboration and large public-private partnerships working toward that goal. Alongside, regulatory bodies like the Center for Disease Control and prevention (CDC) is using multiple strategies for mass serology testings, which include testing different populations at different locations and times, as well as testing donated blood across states for presence of anti-SARS-CoV-2 antibodies. Crucially, serology research is playing a big role in vaccine development- perhaps, the only hopeful means for attaining herd immunity against COVID-19.

Author’s Note:

Volunteering for a COVID-19 serosurvey: An experiential perspective

I was directly involved as a lab-testing volunteer in USA’s first mass seroprevalence study involving 3330 participants led by Stanford Researchers in Santa Clara county of California. It was by far the most impactful episode of my years as a scientist where I had to use my technical expertise for accurate testing, and organizational skills to transform a hotel banquet hall into a functional and safety-compliant makeshift lab. I even wrote a heartfelt article about this mammoth exercise that resonated with a lot of people.  We the volunteers did not have a role in the initial study-design or the final statistical analyses. That being said, I do not write this to free myself of any scientific obligation toward advocating serology studies including the very first one, neither is this a testament in defense of the criticized tools to execute this particular study, like some others. I present this article to address the importance of COVID-19 serosurveys from the balanced perspective of scientific analysis while wearing my ‘volunteer in the nation’s first COVID-19 serosurvey’ badge with pride.

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Author:

Dr. Suvarthi Das is a biomedical scientist and an independent consultant with Ph.D. from Arnold School of Public Health, University of South Carolina, USA, and 3+ years of postdoctoral research experience, the latest being from Stanford University, Gastroenterology and Hepatology. She has been investigating pathways of disease progression specifically in organs like liver, kidney, and gut, for a decade now. In the wake of the COVID-19 pandemic she decided to volunteer her extensive training in molecular biology, immunology, histopathology, viral vector delivery and molecular therapeutics and engage in multiple research projects. Always an artist at heart, Das is also an avid reader and loves hiking and experimental cooking when not doing science.

Editors:

Sumbul Jawed Khan received her Ph. D. in Biological Sciences and Bioengineering from the Indian Institute of Technology Kanpur, where she studied the role of microenvironment in cancer progression and tumor formation. During her post-doctoral research at the University of Illinois at Urbana-Champaign, she investigated the gene regulatory networks that are important for tissue regeneration after damage or wounding. She is committed to science outreach activities and believes it is essential to inspire young people to apply scientific methods to tackle the challenges faced by humanity. As an editor, her aim is to simplify, translate, and excite people about current advances in science.

Illustrator:

Vinita Bharat is a post-doc at Stanford University, USA and had been a PhD student at International Max Planck Research School (IMPRS, Göttingen, Germany). Her research area focuses on cellular and molecular neuroscience. Other than enjoying ‘being a scientist’, she has also been working on science education. Presenting science in an easy and fun way is what she loves doing through her platform “Fuzzy Synapse”. She is a fun, enthusiastic and curious person, passionate about traveling, loves celebrations and bringing smiles around her. Follow her work as Fuzzy Synapse at Instagram, Facebook, and Twitter.