31 May 2022 Blog Post: Making Sense of Antibody Levels

31 May 2022 Blog Post: Making Sense of Antibody Levels

As BA.12.2.1 begins to cut through a wider swath of the population, we are in clinic noticing a significant uptick in cases. This May we have had 27 new cases of COVID-19 in the practice, as opposed to only 4 in April. This has led to a number of questions about booster vaccinations and their role in neutralizing the virus – i.e. stopping its entry into cells and therefore preventing illness.
 
Two studies were published in 2021 based on vaccine trials which connecting neutralizing antibody responses to SARS-CoV-2 with vaccine efficacy allowing for a ‘correlate’ of protection for vaccines (and boosters) against COVID-19. We have discussed these studies in prior posts (Khoury et al. and Earle et al.).
 
Khoury link: Khoury, D.S. et al. Nat. Med. https://doi.org/10.1038/s41591-021-01377-8 (2021).
Earle link: Earle, K.A., et al. Vaccine https://doi.org/10.1016/j.vaccine.2021.05.063 (2021).
 
But before launching into the specifics, let’s take a step back. In general, testing for antibodies is used as a marker of prior infection and recovery. In some cases, such as HIV antibody testing, it can be used to identify an infection (HIV viral load can also be tested to quantify viral activity, the goal being an ‘undetectable’ viral level with treatment). Antibodies are generally long lasting but their interpretation is more complicated than it first appears. They can provide clues about the following:
 
1. When was the person exposed?
2. Has immunity waned or never formed?
3. Was the person exposed or vaccinated?
4. Did the person have the disease or just infection?
 
When antibody testing for SARS-CoV-2 is considered, two main antibody classes are considered:
 
1. 𝐍𝐮𝐜𝐥𝐞𝐨𝐜𝐚𝐩𝐬𝐢𝐝: The viral “coat” that packages the SARS-CoV-2 RNA genome in a protective covering. Antibodies to this protein motif indicate prior community acquired exposure and likely clinical infection with the virus. I have had rare cases of individuals who do not recall having COVID-19 but have positive nucleocapsid antibodies but this is quite unusual. These individuals likely had very mild symptoms and, therefore, went unnoticed. These antibodies do seem to be very long lived as I can still detect nucleocapsid antibodies among those with documented clinical infection as early as March 2020.
2. 𝐒𝐩𝐢𝐤𝐞: This antibody test is used primarily to detect an adaptive immune response to the SARS-CoV-2 vaccine. In some instances, this antibody level may return detectable levels as a result of community acquired infection alone (I have seen this in some patients who were unvaccinated but had the infection). However, SARS-CoV-2 vaccines preferentially target the spike protein of the virus and typically generate a robust quantitative response beyond that seen from infection alone.
 
Using both the nucleocapsid and spike protein antibody results can distinguish between vaccination alone, community-acquired infection alone or infection (primary or breakthrough) and vaccination together.
 
Adding further complexity to this picture is the fact that the spike protein antibody returns a numeric value which can be different based on the performing laboratory. LabCorp for instance returned values up to a maximum of 2500 from the test inception (Summer 2021) through early 2022. However, in 2022 the test parameters changed to accommodate values up to 25,000. Theoretically higher levels of antibody should provide “better” protection against infection but, again, there is significant nuance to the role of these neutralizing antibodies. What we do know is that they protect against severe disease, hospitalization, need for mechanical ventilation and death.
 
Understanding a correlate of protection and, more specifically, an ‘absolute correlate’ (meaning a protective threshold) has significant downstream implications. Firstly, new vaccine candidates (ones that can be made more cheaply and distributed more widely) would not necessarily need to go through expensive clinical trials if they could simply demonstrate that they generate a sufficient immunity threshold. Similarly, those that are immunosuppressed could also quantitatively determine if their vaccine response was sufficient for protection (and if not would be clear candidates for Evushield). Lastly, serosurveys could be undertaken to determine the proportion of the population that has achieved adequate protection.
 
Results for the two studies referenced above showed a significant correlation between vaccine efficacy and vaccine-induced neutralizing antibody activity. But getting at these numbers (spike protein antibody levels), is no easy task. Digging through Supplementary material, Khoury et al suggest the following levels are adequate for protection against symptomatic disease:
 
⊛ Pfizer: 19
⊛ Moderna: 32
⊛ J&J: 105
 
Earle et al. hedge their bets a bit more but suggest the following:
 
⊟ Pfizer: A mean value of 361 (CI: 235, 541) provides 94.6% protection
⊟ Moderna: A mean value of 360 (CI: 273, 476) provides 94.1% protection
⊟ J&J: A mean value of 224 (CI: 158, 318) provides 66.5% protection
 
But here’s the real challenge – these neutralization antibody studies were done during vaccine development, when alpha was the primary circulating variant. As the figure below shows, there has been a steady progression in variants – each seemingly more infectious than the last. That would, logically, mean that a level of 361 providing 94.6% protection against alpha would provide far less protection against Delta or Omicron. But how much less?
 
 
 
 
 
But wait – more bad news. Also, remember too that there is a well described a decline in neutralization titer with time for up to 8 months after SARS-CoV-2 infection or vaccination (perhaps even less with repeated boosters). Frequent re-testing of antibody levels is simply not practical, both at the individual and population levels.
 
So how do we interpret spike protein antibody levels and, more practically, how can we contextualize these levels with protection against infection? Of course, there is no actual answer but here’s my approach.
 
In discussing spike protein antibody levels with patients, I first “benchmark” their results against what might be expected. Although these data are not great, our expectations can be set based on the NIH “Mix and Match” study (which I have also previously discussed). After a primary series and one booster, levels taken two weeks after that second booster are in the 3,000-6,000 range (for the mRNA series which are most typical in the US). Those who have had J&J and add an mRNA booster (one shot, as recommended) can expect levels in the 2,500-3,200 range (Table below). There are no available data on levels after the 2nd booster.
 
In our practice, we are seeing levels anywhere from 3,000 to above 25,000 (this is the upper range). I think at this point, 5,000 should be about the minimum level we should be seeing.
 
And why do I think that should be the minimum? Well let’s look at the data above showing 94% protection against even mild symptomatic disease for Pfizer and Moderna at levels of 360. But Beta was about 50% more transmissible than Alpha. Delta was about twice as transmissible as Beta and Omicron has been estimated to be 5 times more transmissible than Delta. So: 1.5x2x5 = 15.
 
Revising upwards, 360 multiplied by a factor of 15 gives us 5,400.
 
This isn’t terribly scientific and, admittedly, is a decent amount of statistical hand waving. But it does attempt to draw on what we know from the vaccine trials and what we have seen in terms of transmissibility across the subsequent variants.
 
Happy to hear thoughts and rebuttals! Comment below! 

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

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18 May 2022 Blog Post: State of COVID in LA County

It is increasingly difficult to ascertain the contours of the COVID-19 epidemic / pandemic / endemic event in Los Angeles County due to profound shifts in how the Health Department….

18 May 2022 Blog Post: State of COVID in LA County

It is increasingly difficult to ascertain the contours of the COVID-19 epidemic / pandemic / endemic event in Los Angeles County due to profound shifts in how the Health Department collects and tracks testing data. Until recently, case counts could be considered to be fairly accurate as most individuals tested via PCR or rapid antigen test at a medical center or via a laboratory with mandated reporting. Even through the Omicron surge, case counts in the County were more or less reflective of the underlying population trends as (unfortunately) there was a shortage of rapid antigen tests. So rather than testing at home, folks still needed to go to a testing center, medical office or through a reporting laboratory.

As it stands now, most cases (I would imagine at least 50%) are ascertained via home testing and are never reported to the County Health Department by their own case reporting rules. If, for instance, a patient calls my office and lets me know that they are symptomatic and have a positive test – even this is not reportable to the Health Department. If I prescribe them Paxlovid or arrange for monoclonal antibodies?  Still not reportable.

Nevertheless, upon logging into the County Health Department’s COVID-19 webpage, the following information is presented: Case Count, Testing, Testing Positivity Rate, Deaths, Death Rate, and Hospitalizations. Other than Deaths, one could argue that all of the remaining measures are highly skewed. Of concern is that the County (unlike case and testing numbers) does not publish raw hospitalization numbers but instead only provides a graph. Further, there is no discussion of whether or not hospitalized cases are there primarily due to COVID-19 infection or if such is an incidental finding as part of routine surveillance.

Based on the incomplete data that are collected by the County, it does appear that cases are on the rise, increasing from 5.8 new daily cases per 100,000 the week of 3/22/2022 to 23.4 new daily cases per 100,000 the week ending 5/10/2022 (Figure 1 below). This is undoubtedly an undercount of the true number of cases.

The profoundly good news is the continued decline in mortality rates, even in the face of rising cases (Figure 2 below). The County-wide mortality rate due to the infection is now 0.014 daily deaths per 100,000 population. At its highest for the week of 1/10/2021, this rate was 2.79. Expressed differently, for every person that dies in the County today from COVID-19, there were 200 that died in January of 2021.

So what is going on in the County then, in terms of caseload?  One potential clue is from school surveillance data which has been ongoing in Santa Monica / Malibu since the beginning of this year (Figure 3).  One can see that these data seem to be a bit ahead of the County-wide graph which would make sense as both symptomatic and asymptomatic cases would be ascertained. Illustrating such, is that the highest case rate was seen January 1st in the school district but not until January 11th in the County. 

Santa Monica / Malibu Unified School District has noted a steady rise in cases since mid March (note the data gap from April 2-18th due to Spring Break). That upward trend has continued taking the prevalence of positive cases from 0.04% March 5-12th to 1.01% May 9-15th.

At that point in time, there was a shortage of home tests so the incidence case rate for the County was a more accurate reflection of the true rate. With school prevalence of 9% this translated to a County-wide rate of 453 new daily cases per 100,000. Extrapolating to this most recent week, a school prevalence of 1% should mean a population rate of 50.3 new daily cases per 100,000.  The County is reporting half of that at 23.4.

Wastewater surveillance is telling a similar story, at least that the Hyperion plant in Los Angeles. Data collection of gene copies per Liter of wastewater began in early February (Figure 4 below). But similar to the school surveillance detailed above, the lowest gene copy levels were seen Feb 27th (6,579 copies) and March 8th (7,718). This copy level has climbed steadily (with the exception of one outlier on 3/29) and now stands at 216,240. It would have been more helpful to correlate these values with measurements obtained in January of 2021 during the Omicron surge.

So what can we conclude? First, the current caseload reported by the County is inaccurate by at least 2 fold. However, even with this rate adjustment the number of cases are far below that of the January Omicron surge. There is evidence from school surveillance and wastewater that these numbers will push even higher, given the expected lag in case reporting. Despite such, mortality rates continue to decrease which is likely the conjoint effect of vaccination, booster shots, typically mild disease from Omicron subvariants, early detection and early initiation of treatment.

Of course nobody wants to get the infection – but the impact of SARS-CoV-2 in terms of severe disease and mortality has been significantly blunted. Contact tracing efforts would better delineate the extent of transmission (my supposition has been that those who are vaccinated/boosted and treated are not particularly good vectors of spread) as well as the potential role of ‘superspreaders’ at large gatherings. However, the County Health Department has never shown much zeal for this most basic of Public Health activities (current contact tracing is at about 20% and about 85-90% is a reasonable metric for complete case ascertainment). Until somebody decides that it is worth doing contact tracing, we will continue to wonder why some folks get exposed and do not develop the infection (even in close contact, like a household) yet dozens will fall ill after a single celebratory gathering.

 

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3 May 2022: On Roe v. Wade

Yesterday’s leaked Supreme Court majority opinion on overturning Roe v. Wade is, once again, an example of politically appointed officials without public health training making public health decisions

3 May 2022 Blog Post: On Roe v. Wade

Yesterday’s leaked Supreme Court majority opinion on overturning Roe v. Wade is, once again, an example of politically appointed officials without public health training making public health decisions. We saw this in the early days of the COVID-19 pandemic when Riverside County Sheriff Chad Biaco refused to enforce mitigation measures in the County. It is not without some irony that he is listed on the Riverside County website as Sheriff – Coroner (link: https://www.riversidesheriff.org/).

While some will frame it otherwise, a woman’s right to access competent and safe pregnancy termination care is, quite simply, a public health issue. Let me explain why – epidemiologically.

An estimated 25 percent of pregnancies worldwide end in induced abortion. Similarly, in the United States, close to one in four females will have an abortion during their reproductive life. Readers will know that I bristle at percentages, so here are the rates specific to the United States (from CDC data):

  1. The rate of pregnancy termination was 11.3 per 1000 females ages 15 to 44 years, or 189 per 1000 live births. 
  2. The vast majority of pregnancy terminations were performed in the first trimester: 78 percent at ≤9 weeks and 92 percent at ≤13 weeks of gestation. 

The rate of complications associated with pregnancy termination depends on:

  1. Procedure type
  2. Gestational age
  3. Patient characteristics
  4. Clinician experience. 

In general, the risk of a major complication is low. In a retrospective study of California Medicaid data from 54,911 abortion procedures, the overall complication rate was 2.1 percent. The overall death rate from all legal abortions is far less than the maternal mortality rate among live births in the Unites States.  One study reported no maternal deaths in 170,000 consecutive first-trimester suction curettage (D&C) procedures.

Now that we have set the stage – here’s the crucial data.  Maternal mortality in the United States has not improved whatsoever over the past 20 years – this in sharp contrast to the worldwide experience where maternal mortality is falling. US States with restrictions on access to contraception and safe abortion have seen the highest rates in maternal mortality and are the root cause of this stagnation in care (link: https://www.sciencedirect.com/science/article/abs/pii/S0010782421000901). 

Countries with better training of and access to abortion providers have lower maternal mortality rates. A comprehensive study by The Global Health Policy Summit’s Maternal Health Working Group analyzed factors that explained maternal mortality rate decreases of which the most cost-effective interventions were, first, access to contraception, and second, access to safe abortion.

Access to safe abortion care is an essential component of health care. Unfortunately, a large portion of abortions are considered “unsafe,” and these abortions are a major contributor to both maternal morbidity and mortality. The risk of complications and death from unsafe abortion is inversely related to the provider’s training, skill, conditions for performing the procedure, and availability of appropriate equipment. 

At a national level, governments which expanded reproductive health services (like the UK) such as family planning improved women’s health, in the United States, federal and many state governments have done the opposite through restrictive legislation and decreased funding. 

Twenty years ago, the United States and the United Kingdom had the same maternal mortality rate. Currently the United States has a rate about three times that of the United Kingdom

(link: https://dktwomancare.org/article_pdf/VQFbQlSIeXeIhr9NzYnvyDyDFyJKM9LBNI3l5S92.pdf )

As it stands, hundreds of pregnant American women die unnecessarily each year. The Supreme Court can frame their opinion as constitutional law, but in reality, they have strayed far out of their lane. Evidence-based health policies and good reproductive health care from well trained professionals is needed – not a dangerous majority opinion from political appointees.

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