CHEST Resource Center Safety and Efficacy of COVID-19 Vaccines in Patients With Complex Medical Comorbidities

Safety and Efficacy of COVID-19 Vaccines in Patients With Complex Medical Comorbidities


This article is part of CHEST's COVID-19 Resource Center. Please note that the perspectives shared in this article are those of the author(s) and not those of CHEST.

Safety and Efficacy of COVID-19 Vaccines in Patients With Complex Medical Comorbidities

By: Tony T. Ho, MD
Published: June 7, 2021

The emergency use authorization of Pfizer’s SARS-CoV-2 vaccine in December 2020 marked a new chapter in our yearlong struggle against this virus; in the following months, there has been a dizzying amount of data released about the safety and efficacy of available vaccines in recipients with more complex medical comorbidities than just the common ones studied in the phase 3 trials. We’ll look at the data regarding some of the more salient patient populations of interest to pulmonary and critical care medicine.

Prior Infection

One major question is the role of vaccination in the setting of prior COVID-19. We now have several studies demonstrating that a single dose of mRNA vaccine after previous infection yields antibody responses that are markedly elevated compared with their baseline antibody level and similar to the levels obtained from a two-dose regimen.1-8

This phenomenon makes physiological sense. In a conventional multidose vaccine schedule, the first dose generates a primary immune response, and the second dose generates the boosted anamnestic response. In patients with a history of COVID-19, their prior infections will serve as a priming dose of antigen; the first vaccination dose then, in effect, becomes the booster shot.

In addition, several of the above studies make note that the second dose in these situations provides virtually no additional boost to antibody levels. These findings were acknowledged by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) during their March 1, 2021, meeting, but there have been no changes in recommendations for number of doses based on prior COVID-19 positivity yet; this may change in the near future as the data evolve.

Transplant Patients

Transplant recipients are at risk of both severe COVID-19 and for insufficient response to vaccinations due to immunosuppression. In a prospective cohort of solid organ transplant recipients receiving mRNA vaccines, the majority did not mount appreciable anti-spike protein antibody responses 2 weeks after the first dose, when using assays consistently correlated with neutralizing immunity.9

Of interest, recipients of Moderna’s vaccine were significantly more likely to seroconvert after the first dose compared with Pfizer’s. The main difference between the mRNA vaccines is that while Moderna uses mRNA, Pfizer actually uses nucleoside-modified mRNA, or modRNA, where pseudouridine is substituted for uridine. This has two effects: It prolongs the half-life of the mRNA, and it leads to less triggering of the recipient’s Toll-like receptors (TLRs) that would normally be activated by the presence of exogenous ssRNA. This leads to less cytokine release in the host, which can be a bonus in the sense that Pfizer’s vaccine has fewer reactogenic symptoms after immunization in most recipients.10 It is possible, however, that the increased TLR stimulation may lead to better seroconversion with the Moderna vaccine in patients who are immunosuppressed. More studies are needed to confirm this.

Not unexpectedly, antimetabolite therapy (such as mycophenolate) was significantly associated with decreased likelihood of seroconversion, as was increasing age.

A second study in patients with rheumatologic diseases showed similar associations, with decreased seroconversion seen among recipients of antimetabolite therapy and B-cell depleting medications, such as rituximab.11


Biologics, mainly TNF-alpha antagonist medications (and to a lesser degree, others such as vedolizumab), are widely used in the treatment of autoimmune disease. Like patients with organ transplants, this is an area where there is very little data from the trials because use of immunosuppressive medications was an exclusion criterion in most trials. However, the initial data appear promising. One case series of 48 patients with inflammatory bowel disease receiving biologic therapy demonstrated high rates of seroconversion after two doses of the Pfizer vaccine in the 15 patients who completed both doses.12

Antibody Levels

The last two sections have discussed responses with respect to antibody levels; however, some may note that some societies, such as American College of Rheumatology, have recommended not using serological assessment due to lack of data about what a protective level is. This is confounded by the fact that there are several different automated semiquantitative assays available, none of which have comparison values with each other or with a standardized titer; this makes interpretation across assays difficult.

That being said, individual third-party validations of these assays often show high correlation between certain threshold levels on the commercial test and presence of neutralizing activity on viral neutralization assays. For instance, the Roche Elecsys® Anti-SARS-CoV-2 S assay that is popularly used as a semiquantitative assessment for anti-spike proteins was evaluated, and a raw value of 28.7 U/mL on this assay correlated well (>95%) with presence of neutralizing titer >1:5.13

What does this mean? Again, we don’t have data about whether or not this is a protective level; however, I consider it akin to a roller coaster’s “must be this high to ride” sign. It is unproven but logical to consider lack of neutralizing antibody activity to be a marker for inadequate immunity; there are no current guidelines for boosters on top of the existing vaccine series yet, but as with all the issues surrounding the vaccines, I expect more refinement in the near future as more data become available. However, for our patients who are vulnerable and immunosuppressed and who will have difficulty mounting immune responses to the vaccines, the lack of adequate seroconversion would make it reasonable to advise against relaxing of COVID-19 precautions during the pandemic, despite their vaccinated status.

There are some who have said to not worry about antibody levels because what matters is the anamnestic response from the memory T- and B-cells; however, if a second dose of a highly immunogenic vaccine is unable to elicit seroconversion, it would be reasonable to suspect that the population of memory cells is insufficient to render protective immunity.

In fact, when tracking efficacy between the vaccines available both here and abroad, it has been shown that efficacy tracks well with average antibody titer.14

One of the most difficult barriers to overcome in assessing effects is the significant heterogeneity in the susceptible population; however, there was a study with remarkable homogeneity (new recruit Marines, age 18-20, predominantly male) that sheds some light on the level of antibodies necessary for sterilizing immunity. Ten percent of those with preexisting seropositivity became reinfected during their 6-week basic training, but when subdivided down by enrollment antibody titer, those with titers 1:450 and below had a far greater risk of reinfection compared with those with titers above 1:1350, which had nearly zero reinfections. Regardless of contribution by cell-mediated immunity, it appears sterilizing immunity requires high-level antibody titers.15

Cell-Mediated Immunity

Early in the pandemic, there was much discussion about the role of cell-mediated immunity, especially CD8 cytotoxic T-cells. This was based on historical data with SARS and MERS that demonstrated patients with mild disease often had transient or absent antibody levels but robust T-cell response that persisted for years afterward.

However, this hasn’t been shown in the efficacy data; the adenovirus vector vaccines, which are known to stimulate T-cell immunity more robustly than the mRNA vaccines, have markedly lower efficacy (correlating with their significantly lower GMT for antibody titer). Furthermore, despite demonstration that CD8 cells maintain their activity against SARS-CoV-2 across variants, and despite the higher T-cell activation of the ChAdOx1 vaccine from AstraZeneca, there is almost complete loss of effectiveness when used in an area with B.1.351 prevalence, such as South Africa.16-17

On the flip side, Sinopharm’s vaccine (an inactivated SARS-CoV-2 vaccine with alum adjuvant) has reported 80%-86% efficacy in China and the United Arab Emirates. However, there were no changes in T-cell cytokine distribution; while the study specifically doesn’t measure CD8 stimulation, we know from prior vaccines that alum is a poor stimulator of T-cell response in humans.18

Finally, it is exceedingly rare to assess T-cell response in clinical practice; the only common use of these assays are the interferon-gamma release assays for tuberculosis. These assess only exposure, not immunity.

In conclusion, T-cell activity does not appear to be as associated with immunity and vaccine efficacy as previously hoped; this, with the fact that it isn’t currently possible to even test for T-cell activity level in a clinical setting, leads to my belief that antibody levels will be a more useful gauge with which to assess degree of protection. As with all things COVID, though, this may change as we get more data.

Women of Childbearing Age

On April 13, 2021, the Food and Drug Administration and the CDC released a joint statement recommending a pause in the use of Johnson & Johnson’s COVID-19 vaccine due to six cases of a rare clotting phenomenon known as cerebral venous sinus thrombosis.19 These cases occurred in women of reproductive age (18-49) and within 6-14 days of the vaccination.

Subsequently, this syndrome has been called thrombosis with thrombocytopenia syndrome, or TTS. By April 23, 2021, a total of 15 cases were identified amongst recipients of the Johnson & Johnson vaccine, with no cases identified with either Pfizer or Moderna vaccines. Due to the exceptional rarity of cases and projections that holding the vaccine further would lead to more deaths from COVID-19, ACIP recommended reinstatement of use for this vaccine, and Johnson & Johnson reported they agreed to warning language with the FDA noting the risks of TTS in women under age 50.

Of note, even though the risk of this complication appears heavily weighted toward women, at least two male recipients of Johnson & Johnson’s vaccine have developed TTS; one was a 26-year-old man in the phase 3 trial, which led to a brief trial pause. The second was reportedly a man in his 30s in the San Francisco Bay area.20


The field of COVID-19 vaccines is ever changing as we get new data regarding their performance in specific patient populations. There are several areas where more data are desperately needed, but as we fill in those gaps slowly, we will be able to best personalize our recommendations for our patients and their unique situations.


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  2. Ciccone EJ, Zhu DR, Ajeen R, et al. SARS-CoV-2 seropositivity after infection and antibody response to mRNA-based vaccination. medRxiv. Preprint. Posted online February 22, 2021. doi:10.1101/2021.02.09.21251319
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  9. Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA. 2021;325(17):1784-1786.
  10. Karikó K, Buckstein M, Ni H, et al. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005;23(2):165-175.
  11. Braun-Moscovici Y, Kaplan M, Markovits D, et al. Humoral response to Pfizer mRNA vaccine against SARS CoV2, in patients with autoimmune inflammatory rheumatic diseases and the impact on the rheumatic disease activity. medRxiv. Preprint. Posted online April 6, 2021. doi:10.1101/2021.04.02.21254493
  12. Wong S-Y, Dixon R, Pazos VM, et al. Serological response to COVID-19 vaccination in IBD patients receiving biologics. medRxiv. Preprint. Posted online March 10, 2021. doi:10.1101/2021.03.17.21253848
  13. Rubio-Acero R, Castelletti N, Fingerle V, et al. In search for the SARS-CoV-2 protection correlate: a head-to-head comparison of two quantitative S1 assays in a group of pre-characterized oligo-/asymptomatic patients. medRxiv. Preprint. Posted online February 23, 2021. doi:10.1101/2021.02.19.21252080
  14. Earle KA, Ambrosino DM, Fiore-Gartland A, et al. Evidence for antibody as a protective correlate for COVID-19 vaccines. medRxiv. Preprint. Posted online March 20, 2021. doi:10.1101/2021.03.17.20200246
  15. Letizia AG, Ge Y, Vangeti S, et al. SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study. Lancet Respir Med. Preprint. Posted online April 15, 2021. doi:10.1016/S2213-2600(21)00158-2
  16. Redd AD, Nardin A, Kared H, et al. CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants. medRxiv. Preprint. Posted online February 12, 2021. doi:10.1101/2021.02.11.21251585
  17. Madhi SA, Baillie V, Cutland CL, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N Engl J Med. 2021;384(20):1885-1898. doi:10.1056/NEJMoa2102214
  18. Del Giudice G, Rappuoli R, Didierlaurent AM. Correlates of adjuvanticity: a review on adjuvants in licensed vaccines. Semin Immunol. 2018;39:14-21.
  19. Centers for Disease Control and Prevention. Joint CDC and FDA statement on Johnson & Johnson COVID-19 vaccine. Centers for Disease Control and Prevention; 2021. Accessed April 30, 2021.
  20. Torrez J. UCSF confirms man experienced blood clots after receiving Johnson & Johnson vaccine. KTVU FOX 2. April 26, 2021. Accessed April 30, 2021.

Tony T. Ho, MD

Tony T. Ho, MD

Dr. Ho is an Assistant Professor/Clinical at UT Health San Antonio in the Division of General and Hospital Medicine and South Texas Veterans Health Care System.