Scientists have published the first analysis of how four types of COVID-19 vaccines prepare the body to fight SARS-CoV-2


Scientists at La Jolla Institute for Immunology (LJI) have published the first analysis of how four types of COVID-19 vaccines prepare the body to fight SARS-CoV-2. Their in-depth look at how T cells, B cells, antibody levels shift in the six months following vaccination is critical for understanding of how to protect people in the ongoing pandemic.

The new investigation, published in Cell, is the first study in history to compare how three different vaccine platforms trigger an immune response against the same pathogen.

“This study is important because it lets us answer how different vaccine platforms perform in terms of inducing immune responses,” says LJI Professor Alessandro Sette, Dr. Biol. Sci.

The researchers studied human immune responses to an mRNA platform (Pfizer-BioNTech and Moderna vaccines), a recombinant protein-based adjuvanted vaccine platform (Novavax), and a viral vector-based platform (Janssen/J&J). All four vaccines in this study were designed to prepare the immune system to fight the same target, called the SARS-CoV-2 Spike protein.

“We aren’t giving a vaccine scorecard,” says LJI Research Assistant Professor Daniela Weiskopf, Ph.D., who co-led the study with Sette and LJI Professor Shane Crotty, Ph.D. “This kind of side-by-side analysis has never been done before with people who received different vaccines at the same time – in a real life setting. Just understanding the immune responses to these vaccines will help us integrate what is successful into vaccine designs going forward.”

Key findings:

  • Antibodies: After six months, those given Moderna had highest levels of neutralizing antibodies, followed by those given the Pfizer-BioNTech and Novavax vaccines. The Janssen/J&J vaccine led to the lowest neutralizing antibody levels.
  • B cells: Participants given the Janssen/J&J vaccine had the highest percentage of memory B cells after six months.
  • CD4+ T cells: All participants retained a similar percentage of memory CD4+ “helper” T cells against the virus.
  • CD8+ T cells: The Novavax vaccine led to the lowest levels of CD8+ “killer” T cells. A higher CD8+ response was seen in those given Pfizer-BioNTech, Moderna, or Janssen/J&J vaccines. Overall, after six months, only 60 to 70 percent of participants retained memory CD8+ T cells.


COVID-19 vaccines have achieved extraordinary success in protection from infection and disease; yet some limitations exist, including differences in VE between vaccines and waning of protection against infection over a period of several months. Here, diverse metrics of adaptive responses were measured to mRNA-1273, BNT162b2, Ad26.COV2.S and NVX-CoV2373, with implications for understanding the protection against COVID-19 associated with each of the vaccines.

A strength of this study is that the samples from different vaccine platforms were obtained from the same blood processing facility, from the same geographical location, and were analyzed concomitantly, utilizing the same experimental platform.

In the present study, antibody responses were detected in 100% of individuals. At 6 months post-immunization, the neutralizing antibody titer hierarchy between the vaccines was mRNA-1273~BNT162b2~NVX- CoV2373>Ad26.COV2.S. These serological data are consistent with previous reports for single vaccines (Atmar et al., 2022; Doria-Rose et al., 2021; Goel et al., 2021; Naranbhai et al., 2021a; Pajon et al., 2022; Pegu et al., 2021), and serological comparisons between vaccines (Barouch et al., 2021; Carreno et al., 2022; Dashdorj et al., 2021; Lafon et al., 2022; Naranbhai et al., 2021b; Self et al., 2021) , though in much larger serological studies ~2-fold higher neutralizing antibody titers were discerned with mRNA-1273 compared to BNT162b2 (Atmar et al., 2022; Steensels et al., 2021). Comparisons of NVX-CoV2373 antibody responses compared to other vaccines after 6 months have been very limited. Here we observed that NVX-CoV2373 neutralizing antibody titers were comparable to that of BNT162b2 and only moderately lower than mRNA-1273.

In this side-by-side comparative study, spike-specific CD4+ T cell responses were detected in 100% of individuals to all four vaccines. While neutralizing antibody kinetics were different between mRNA and viral vector vaccines, the CD4+ T cell response kinetics were similar.

The hierarchy of the magnitude of the memory CD4+ T cells was mRNA-1273>BNT162b2~NVX-CoV2373>Ad26.COV2.S. These overall findings are consistent with previous reports on COVID-19 vaccine T cell responses (Barouch et al., 2021; Goel et al., 2021; Guerrera et al., 2021; Khoo et al., 2022; Liu et al., 2022; Mateus et al., 2021; Rodda et al., 2022; Tarke et al., 2022), but the analysis reported herein extensively expand these observations, including four different vaccines representing three different vaccine platforms, and with longitudinal data and single-cell cytokine expression resolution providing insights regarding CD4+ T cell subpopulations between the vaccines. Interestingly, multifunctional CD4+ T cells were observed most frequently after mRNA-1273 immunization, and GzB+ early CD4-CTLs represented a substantial fraction of the memory CD4+ T cells after mRNA-1273, BNT162b2, or NVX-CoV2373 vaccination.

cTfh memory cells were represented as a substantial fraction of CD4+ T cell memory for each of the 4 vaccines, consistent with these vaccine platforms being selected for their ability to induce antibody responses.

Memory CD4+ T cell responses were also compared to infected individuals, demonstrated that each vaccine was successful in generating circulating spike- specific CD4+ T cell memory frequencies similar to or higher than SARS-CoV-2 infection, though of course infection also generates responses to other viral antigens.

The two mRNA vaccines and Ad26.COV2.S induced comparable acute and memory CD8+ T cell frequencies. These data are broadly consistent with previous reports for mRNA vaccines or adenoviral vectors (Goel et al., 2021; Guerrera et al., 2021; Keeton et al., 2022; Mateus et al., 2021; Tarke et al., 2022), with the exception being represented by reduced cytokine-expressing CD8+ T cells detected after mRNA vaccinations when using a 6 to 8-hr assay (Atmar et al., 2022; Collier et al., 2021), compared to the overnight stimulation used here. As expected for a protein-based vaccine, IFNg+ memory CD8+ T cell frequencies after NVX-CoV2373 were lower than the other vaccine platforms assessed, but it was notable that NVX-CoV2373 generated spike-specific CD8+ T cell memory in a significant fraction of individuals, and the IFNg+ spike-specific memory CD8+ T cell frequencies were similar at 6 months between NVX-CoV2373 immunizations and SARS-CoV-2 infection.

Spike- and RBD-specific memory B cell responses were detected in all individuals to each of the four vaccines. While neutralizing antibody titers declined over time in mRNA vaccinees, the frequency of spike-specific memory B cells increased over time. These divergent antibody and memory B cell kinetics were also observed in SARS-CoV-2 infection (Dan et al., 2021). The mRNA vaccine data are comparable to Goel et al. (Goel et al., 2021), but memory B cell data and kinetics for the Ad26.COV2.S or NVX-CoV2373 vaccines have not previously been available. At 6 months post-immunization, the spike-specific memory B cell hierarchy was

mRNA1273~BNT162b2>Ad26.COV2.S>NVX-CoV2373. One of the most differentiating features of Ad26.COV2.S immunization observed here was the high frequency of CXCR3+ memory B cells. CXCR3+ memory B cells were correlated with neutralizing antibody titers after Ad26.COV2.S immunization, but not mRNA immunization, suggesting a specific functional role in viral vector B cell responses. CXCR3 expression was present on most memory B cells after SARS-CoV-2 infection (Fig. S6G). CXCR3 expression on memory B cells has been found to be important for mucosal immunity in two mouse models (Oh et al., 2019; Oh et al., 2021). CXCR3 ligands are also expressed in infection-induced IFNg inflammation in non-mucosal sites.

Between the mRNA vaccines, mRNA-1273 elicited more immune memory than BNT162b2. Vaccine dose and timing are likely explanations for the observed differences. mRNA-1273 contains 100 µg mRNA, while BNT162b2 contains 30 µg. In a clinical trial of mRNA-1273, a 25 µg dose elicited somewhat lower neutralizing antibody and memory CD4+ T cell responses than the 100 µg dose (Mateus et al., 2021) and the differences between 25 µg and 100 µg mRNA-1273 were comparable to the differences observed here between 100 µg mRNA-1273 and 30 µg BNT162b2. The time interval between the 1st and 2nd mRNA dose may also contribute to the differences in the frequencies and phenotypes of memory T cells between mRNA1273 and BNT162b2. Memory T cells with high proliferative potential are typically not generated until several weeks after a 1st immunization (Sallusto et al., 2010)

; thus a 2nd immunization prior to maximal establishment of memory T cells after the 1st dose may contribute to sub- optimal T cell memory later. A longer time interval likely also contributes to higher quality memory B cell responses, as observed for SARS-CoV-2 infection and vaccines (Cho et al., 2021; Muecksch et al., 2022) , and other contexts (Lee et al., 2021).

Across the antigen-specific immune metrics assessed, mRNA vaccines were consistently the most immunogenic, with levels higher than or equal to that of Ad26.COV2.S and NVX-CoV2373 vaccines for each immune response. NVX-CoV2373 elicited CD4+ T cell memory and neutralizing antibody titers comparably to the mRNA vaccines. The responses induced by the Ad26.COV2.S were generally lower but relatively stable. The mRNA vaccine platforms were associated with substantial declines in neutralizing antibody titers over 6 months, while memory CD4+ T cells, memory CD8+ T cells, and memory B cells exhibited small reductions (T cells) or increases (B cells). These observations appear to be consistent with the relatively high degree of protection maintained against hospitalizations with COVID-19 after these vaccines over 6 months, and the differential VE reported between mRNA COVID-19 vaccines and Ad26.COV2.S. These results of detailed immunological evaluations, coupled with analyses of VE data published for the various vaccine platforms, may also be relevant for other vaccine efforts.

reference link : More information: Zeli Zhang et al, Humoral and cellular immune memory to four COVID-19 vaccines, Cell (2022). DOI: 10.1016/j.cell.2022.05.022


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