Saturday, June 20, 2020

COVID-19: From here To Immunity (Take Two)


A little more than 16 weeks ago, in Osaka Japan: `Recovered' Patient Tests Positive For COVID-19, we looked at initial reports suggesting that some patients might not develop robust antibodies following SARS-CoV-2 infection, and might be reinfected.
The patient, a tour bus guide in Osaka - who was hospitalized with COVID-19 in late January and released from the hospital on Feb. 6th after testing negative - tested positive again 3 weeks later.
Of course, reinfection wasn't the only possible explanation. It is possible that the tests used to clear her for discharge simply weren't sensitive enough to pick up a lingering, low grade, infection. In that case, this could have been a relapse, not a reinfection.
And given the poor performance of lab testing, and the high number of false negatives see COVID-19 Testing: When `No' Doesn't Always Mean No), a relapse seemed the more likely explanation. 
But at the time, I also mentioned studies on a small cohort of MERS-CoV cases in Saudi Arabia (see (see EID Journal: Antibody Response & Disease Severity In HCW MERS Survivors) that found limited, and relatively short-lived antibody titers, particularly in those who did not have severe disease.

Specifically, the study looked at 9 Health care workers who were infected during the 2014 Jeddah outbreak (2 severe pneumonia, 3 milder pneumonia, 1 URTI, and 3 asymptomatic), that found only those with severe pneumonia still carried detectable levels of antibodies 18 months later.
Those who experienced a milder pneumonia had shorter lived antibody responses (1 out to 10 months, 2 out to 3 months), while the URTI and asymptomatic cases tested negative at 3 months post infection.
It should be noted that immunity studies (without challenge) following the 2002-2003 SARS outbreak (see Long-Term Persistence of IgG Antibodies in SARS-CoV Infected Healthcare Workers) have been far more encouraging, with comforting levels of antibodies detected up to 12 years after exposure. 

Seven weeks later, in COVID-19: From Here To Immunity, we revisited that study and several others following an opinion piece published by the New York Times by Dr. Marc Lipsitch that went over the still slim and sometimes conflicting evidence for acquired immunity from COVID-19 infection, along with some of the challenges of creating a vaccine.

It's a very good read, although not particularly reassuring. The short version is; it's complicated.

Follow the link to read the unabridged version.
Who Is Immune to the Coronavirus?
Important decisions about this question are being made, as they must be, based on only glimmers of data.
By Marc Lipsitch

Given than herd immunity - either from natural infection or a vaccine - is needed if we are to control this pandemic, and keep SARS-CoV-2 from becoming a seasonal scourge, these early reports have been concerning.

In late April, in WHO Scientific Brief: `Immunity Passports' For COVID-19, the World Health Organization added an additional caveat, stating:
There is currently no evidence that people who have recovered from COVID-19 and have antibodies are protected from a second infection.
In the past week, we've seen a couple more studies on point, both of which raise concerns over the incidence, durability and effectiveness of post SARS-CoV-2 infection antibodies. 

First, from the pre-print server MedRxiv, a study that finds - like we saw with the 2016 MERS-CoV study - that patients with mild illness often don't develop as robust of an antibody response as those with severe disease.

And some small percentage of patients, never seroconverted at all.
Dynamics of IgG seroconversion and pathophysiology of COVID-19 infections
Henry M Staines, Daniela E Kirwan, David J Clark, Emily R Adams, Yolanda Augustin, Rachel L Byrne, Michael Cocozza, Ana I Cubas-Atienza, Luis E Cuevas, Martina Cusinato, Benedict M O Davies, Mark Davis, Paul Davis, Annelyse Duvoix, Nicholas M Eckersley, Daniel Forton, Alice Fraser, Gala Garrod, Linda Hadcocks, Qinxue Hu, Michael Johnson, Grant A Kay, Kesja Klekotko, Zawditu Lewis, Josephine Mensah-Kane, Stefanie Menzies, Irene Monahan, Catherine Moore, Gerhard Nebe-von-Caron, Sophie I Owen, Chris Sainter, Amadou A Sall, James Schouten, Chris Williams, John Wilkins, Kevin Woolston, Joseph R A Fitchett, Sanjeev Krishna, Tim Planche
We report dynamics of seroconversion to SARS-CoV-2 infections detected by IgG ELISA in 177 individuals diagnosed by RT-PCR. Longitudinal analysis identifies 2-8.5% of individuals who do not seroconvert even weeks after infection. They are younger than seroconverters who have increased co-morbidity and higher inflammatory markers such as C-Reactive Protein. Higher antibody responses are associated with non-white ethnicity. Antibody responses do not decline during follow up almost to 2 months. Serological assays increase understanding of disease severity. Their application in regular surveillance will clarify the duration and protective nature of humoral responses to SARS-CoV-2.

A press release from St. Georges University goes into more detail:
COVID-19 immune response may remain stable for two months after diagnosis
by St. George's University of London
The results demonstrate that in those patients with an antibody response, the levels remained stable for the duration of the study (almost two months). The study also shows that those patients with the most severe infections having the largest inflammatory response were more likely to develop antibodies.
The researchers suggest that this may be due to antibody responses working in parallel with an inflammatory response to severe disease, or that a higher viral load could lead to greater stimulation of the inflammatory and antibody development pathways. Further mechanistic work is required to understand if and why this may be the case.
Between 2 and 8.5% of patients did not develop COVID-19 antibodies at all. The researchers indicate this may be because the immune response in these patients could be through other immune response mechanisms, such as different antigens or T-cells. Another option could be that relatively mild infections may be restricted to particular locations in the body, such as within mucosal cells of the respiratory tract, where antibody responses are instead dominated by a secretory immune system.
The study also explored associations between different characteristics and antibody responses. Being of non-white ethnicity was associated with a higher antibody response, tying into the knowledge that patients from BAME backgrounds are more likely to develop severe disease. Older patients and those with other conditions, such as with hypertension and being overweight were also more likely to have an antibody response.
          (Continue . . . )

The second study, presented in a letter this week to Nature Medicine, found a far lower rate of detectable virus specific antibodies 8 weeks following release from the hospital. Again, asymptomatic cases had significantly lower antibody levels compared to symptomatic patients.

First a link to the study, then some excerpts from last night CIDRAP summary by Robert Roos.
Published: 18 June 2020
Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections
Quan-Xin Long, Xiao-Jun Tang, Qiu-Lin Shi, Qin Li, Hai-Jun Deng, Jun Yuan, Jie-Li Hu, Wei Xu,Yong Zhang, Fa-Jin Lv, Kun Su, Fan Zhang, Jiang Gong, Bo Wu, Xia-Mao Liu, Jin-Jing Li, Jing-Fu Qiu, Juan Chen & Ai-Long Huang
Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.
          (Continue . . . . )

A link and an excerpt from the CIDRAP report but you'll want to read it in its entirety:
Chinese study: Antibodies in COVID-19 patients fade quickly
Filed Under: COVID-19Robert Roos | News Writer | CIDRAP News |
Jun 19, 2020
A new study from China showed that antibodies faded quickly in both asymptomatic and symptomatic COVID-19 patients during convalescence, raising questions about whether the illness leads to any lasting immunity to the virus afterward.
The study, which focused on 37 asymptomatic and 37 symptomatic patients, showed that more than 90% of both groups showed steep declines in levels of SARS-COV-2–specific immunoglobulin G (IgG) antibodies within 2 to 3 months after onset of infection, according to a report published yesterday in Nature Medicine. Further, 40% of the asymptomatic group tested negative for IgG antibodies 8 weeks after they were released from isolation.
The authors said the findings suggest that it could be risky to assume that recovered patients are immune to reinfection, which may have implications for how long to maintain physical distancing restrictions.
(Continue . . . )

Four months ago it verged on heresy to suggest that infection and recovery from SARS-CoV-2 might not result in a robust, and long-lasting immunity in humans. Today - while the the jury is still out - the notion isn't nearly as unthinkable as it once was.

Virus-specific antibodies aren't the only immune defense human hosts can mount again reinfection.  As Robert Roos mentions in his report:
The study did not address cellular immunity to COVID-19—that is, immune responses involving T-cells rather than antibodies. Some previous studies have found SARS-CoV–specific T-cells in high percentages of convalescent COVID-19 patients.
But whether that is enough to get us from here to immunity, is far from certain.