The Leukemia & Lymphoma Society (LLS) has published the results of its Patient Registry study measuring (i) T cell responses to the Covid mRNA vaccines in 505 blood cancer patients who had received two mRNA vaccines and (ii) the extent to which a third mRNA vaccine boosted the antibody response in 1080 patients. In this post, I’ll do my best to summarize the LLS findings as accurately as I can as a layperson. I’m neither a scientist nor a physician, though, so please keep this in mind.

A Tiny Bit of Background re B and T Cells

A healthy immune system will produce Covid-specific B and T cells in response to vaccination or infection.  These are two of the most important weapons a body has against the virus. 

Covid-specific B cells can produce antibodies capable of binding to the Covid virus, some (but not all) of which “neutralize” the virus by preventing it from entering the person’s cells.  (There are other ways antibodies can help clear an infection that are too complicated to go into here.) A wide spectrum of antibodies are produced through a process analogous to “trial and error.” Many of these can bind to the virus, but are not effective in helping to clear the virus. Tests like the LabCorp SARS-CoV-2 Semi-Quant Total Ab test measure all antibodies that can bind to the spike protein of the virus, not just the antibodies that neutralize it. 

Generally speaking, the more antibodies a person has on the LabCorp test, the more likely it is that their immune system produced neutralizing antibodies. As explained more below, there is evidence that people with LabCorp results below 100 AU/mL or even 250 AU/mL are unlikely to have produced neutralizing antibodies. (In addition, antibodies that neutralize the original virus may not neutralize later variants. So, even a significant antibody response to vaccination may not include antibodies that can quickly neutralize a later variant.)

Covid-specific T cells fight the virus by destroying infected cells. There are no readily available commercial T cell tests at this time.

Ideally, neutralizing antibodies and Covid-specific T cells work together along with other components of the immune system to eliminate infection.

The Results in a Nutshell

• 58% of participants who were sero-positive (i.e., who produced spike antibodies) after two mRNA vaccines also produced Covid-specific T cells.
• Only 45% of those who were sero-negative (i.e, who did not produce spike antibodies) produced T cells.
• When low antibody responders (below 100 AU/mL on the LabCorp test) were lumped together with participants who were sero-negative, 56% of the combined group had no T cells.  This indicates that low antibody responders are less likely to produce T cells than more robust responders.
• Only 22% of participants who were sero-negative after their second vaccine produced antibody levels above 100 AU/mL after their third shot. (Those below 100 AU/mL after vaccine #3 probably did not produce a meaningful number of neutralizing antibodies.)
•  97% of participants who were sero-positive after two shots “had markedly elevated anti-spike antibody levels” after their third shot. 2.4% had antibody levels below 100 AU/mL after their third vaccination indicating they probably did not produce neutralizing antibodies.

T Cell Results in More Detail

The LLS T cell study included 285 people with Chronic Lymphocytic Leukemia, 154 with non-Hodgkins Lymphoma, 20 with Hodgkins Lymphoma and 17 with Multiple Myeloma. Most (338) were 65 years of age or older. All participants had received two doses of the Pfizer or Moderna Covid vaccines at the time their blood was sampled for this study.

LLS was interested in whether there is a relationship between the participants’ antibody and T cell responses.  It, therefore, divided them into two groups: those who produced no Covid antibodies after two vaccines (“sero-negative”) and those who produced at least some antibodies  (“sero-positive”). As in past LLS reports, for this initial analysis, participants were considered “sero-positive” even if their  antibody test result was barely above the .8 AU/mL cut-off on the LabCorp SARS-CoV-2 Semi-Quant Total Ab test.  

Analyzing the T cell response in these two groups, LLS found that 58% of the sero-positive participants produced Covid-specific T cells while only 45% of those who were sero-negative had done so. Neither patient age nor treatment with BTK inhibitors, anti-CD20 antibodies, or Venetoclax seemed to significantly affect the rate of T cell positivity.  (Very few patients had received chemo or steroid treatments so LLS was unable to assess their impact on T cell response.)

This table provides the results of the T cell study for each blood cancer. Note that the results for some participants were “T Cell No Call.” This means that no definite conclusion could be drawn as to whether Covid-specific T cells were present. However, as these participants had “a significantly lower T cell fraction compared to other samples, likely due to their hematological disease or prior therapy,” they are are considered to be “T Cell Non-Positive” and likely to be “at an elevated risk of infection or severe disease due to reduced vaccine immunogenicity.”

When LLS looked at the breadth of spike-specific T cells, it found greater breadth in participants who had received the Moderna mRNA vaccine as compared with the Pfizer shot.

Research has shown that low “positive” results on the LabCorp test are unlikely to correspond to the presence of antibodies that actually neutralize the virus.   Remember, there’s a trial and error aspect to antibody production. Therefore, until the body has produced a large number of antibodies, it is unlikely that it will have produced many that actually work to prevent infection. For this reason, a person can have a low positive result on an antibody test without having any neutralizing antibodies.  Noting this, LLS looked at the T cell levels in a third group which included both participants who were “seronegative” and those whose antibodies were below 100 AU/mL on the LabCorp test (“low responders”).

When low antibody responders (below 100 AU/mL) and “sero-negative” participants were grouped together, 56% of this group had no T cells.  This would indicate that low responders, like those who are sero-negative, are less likely to produce T cells than people with an antibody response above 100 AU/mL.

I was happy to see that, in this latest paper, LLS acknowledged that a low antibody response might not correlate with the presence of neutralizing antibodies. In its past reports, LLS classified anyone who scored above the LabCorp cut-off of .8 AU/mL as sero-positive. I believe this made Covid vaccines appear more effective in blood cancer patients than they probably are. In fact, there is some evidence that people with antibody levels between 100 AU/mL and 250 AU/mL may also lack sufficient neutralizing antibodies to fight off Covid infection.  Dr. Dorry Segev, who studies vaccine response in organ transplant recipients and conducted the research that led to a third vaccine for the immunocompromised, has found that, in his patient population, “until you reach 250 units/mL, you have little evidence of neutralization.” Anecdotally, I was told by an infectious disease doctor who worked with Dr. Segev that this likely applies to blood cancer patients as well.

More Detail re the Impact of a Third Vaccine on Antibody Levels

In addition to measuring T cells, LLS looked at the extent to which a third Covid vaccine boosted the antibody response of blood cancer patients.  This time, the cohort included 1080 participants, most of them with a B cell malignancy.

After the third vaccine, 40% of participants went from sero-negative to sero-positive (i.e., they “seroconverted”). However, “only 22% of patients who had no detectable anti-S antibodies after the second vaccination produced antibody levels >100 AU/mL after the third SARS-CoV-2 mRNA vaccine dose.” In other words, LLS is saying it is likely that only 22% of participants who were sero-negative after two shots actually produced neutralizing antibodies after their third shot. If the real cut-off for presence of meaningful numbers of neutralizing antibodies is 250 AU/mL, as Dr. Segev and his colleagues maintain, then the percentage of sero-negative who may have produced neutralizing antibodies from their third shot is probably even lower.

Of participants who were sero-positive after two vaccines, 97% “had markedly elevated anti-spike antibody levels” after their third shot.  The median antibody level for this group before their third vaccine was 231 AU/mL.  After the third shot, the median was 2500 AU/mL.  2.4% had antibody levels at or below 100 AU/mL after their third vaccination and a few saw their antibody levels decrease following vaccine #3.

LLS found that, “in general, in our cohort impaired responses to the third vaccination were greatest in patients with B cell-derived malignancies, except for patients with multiple myeloma or Hodgkin lymphoma, who responded well. Moreover, unlike T-cell responses, LLS found that antibody responses were depressed by B cell-directed therapies.

In its summary, LLS observed it had identified “patients with hematologic malignancies with no or low spike-directed T cell and antibody responses after two SARS-CoV-2 mRNA vaccinations, and those with persistent lack of serological responses after three vaccinations. Such patients may be at the greatest risk of infection or severe COVID-19. Alternative preventive and therapeutic approaches, including the use of monoclonal antibodies or antiviral drugs, may be justified in patients with hematologic malignancies.”