The Pfizer-BioNtech and Moderna COVID-19 vaccines will likely provide protection against the coronavirus for years if it doesn't evolve significantly, a small new study suggests.
As a massive vaccination effort continues to play out across the globe, there is still a question about how protective COVID-19 vaccines will be in the long term and whether booster shots will be necessary. Some vaccines for other viruses, such as influenza, provide only fleeting protection and need to be renewed every year, but others — such as the MMR vaccine for measles, mumps and rubella — confer lifelong protection.
The level of protection depends on how much and how quickly the virus evolves, as well as on how robust different types of vaccines are in spurring a lasting immune response. The Pfizer-BioNTech and Moderna vaccines both use a relatively novel platform known as messenger RNA (mRNA) to train the immune system to fight SARS-CoV-2, the virus that causes COVID-19, Live Science previously reported.
While mRNA vaccines have greatly exceeded experts' expectations and have shown high efficacy in protecting people from SARS-CoV-2, including its currently circulating variants, how long this protection will last hasn't been clear.
To figure this out, a group of researchers recruited 41 participants who received two doses of the Pfizer-BioNTech vaccine; eight had previously been infected with SARS-CoV-2. The researchers collected blood samples at the start of the study and then three, four, five, seven and 15 weeks after the participants received their first dose of the vaccine.
Consistent with previous studies, the researchers found that the mRNA vaccine induced strong antibody responses and that those responses were even stronger in people who had recovered from a mild SARS-CoV-2 infection prior to being vaccinated.
The team also collected lymph node samples across this same time span from 14 people, none of whom had previously been infected with SARS-CoV-2. In response to infections and vaccinations, fleeting molecular structures known as "germinal centers" form inside the lymph nodes, the glands that hold immune system cells and typically swell in response to an infection.
In people who are infected with SARS-CoV-2, these structures form in the lymph nodes of the lungs, which are difficult to access, whereas vaccines typically spur their production in the armpits, which is more easily accessible.
"You can think of them as our boot camps for the immune cells," said senior author Ali Ellebedy, an immunologist at the Washington University School of Medicine in St. Louis. The structures train a type of immune cell known as B cells over weeks and months to bind better to a pathogen — in this case, SARS-CoV-2.
The process creates highly trained immune cells, some of which are memory cells that will remember the virus in the long-term.
Not much is known about how long these "boot camps" last inside the lymph nodes in humans; animal studies have shown that they typically last only a few weeks, Ellebedy said.
But in the new study, Ellebedy and his team found something surprising: In most of the participants who received the vaccine, their germinal centers continued to be active, training these robust immune cells for at least 15 weeks after the first dose.
'Very promising' protection Because this germinal-center response lasted for months, it likely produced many memory cells that will last for years; and some of these memory cells will likely establish themselves inside bone marrow and produce lifelong antibodies, Ellebedy told Live Science. That's "very promising" but doesn't necessarily mean people won't need booster shots, he said.
Rather, the need for booster shots will depend on how much the virus evolves and whether the cells produced by the germinal centers are robust enough to handle significantly different variants, he added. In addition, not everyone generates the same robust immune response; some people, such as those with suppressed immune systems, will likely need booster shots, he said.
"This study, like others before it, confirms that the vaccines are eliciting the appropriate reaction from the immune system and that durable immunity is being created," said Dr. Amesh Adalja, an infectious-diseases specialist and a senior scholar at the Johns Hopkins Center for Health Security in Baltimore.
Adalja, who was not involved in the new study, agrees that it's too soon to discuss whether we will need booster shots. "If a large proportion of the fully vaccinated are contracting breakthrough infections that land them in the hospital, that is the threshold for booster vaccinations," he told Live Science in an email.
Still, this is the first study to provide direct evidence that the germinal-center response is persistent in humans after vaccination. Although the authors didn't look at people who had received the Moderna vaccine, they think the response will likely be similar, because it's also an mRNA vaccine that showed a comparable efficacy, Ellebedy said. However, more research will be needed to see the duration of the germinal-center response from the Johnson & Johnson vaccine, because it uses a different platform (rather than mRNA), he said.
Now, Ellebedy and his team hope to continue monitoring these cells to see whether they migrate and settle permanently in bone marrow. In other words, it's still unclear whether these immune cells will "become our life partners, basically helping us for the rest of our lives" or if we will eventually need booster vaccines to make some better fighters.
SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses Jackson S. Turner, Jane A. O’Halloran, Elizaveta Kalaidina, Wooseob Kim, Aaron J. Schmitz, Julian Q. Zhou, Tingting Lei, Mahima Thapa, Rita E. Chen, James Brett Case, Fatima Amanat, Adriana M. Rauseo, Alem Haile, Xuping Xie, Michael K. Klebert, Teresa Suessen, William D. Middleton, Pei-Yong Shi, Florian Krammer, Sharlene A. Teefey, Michael S. Diamond, Rachel M. Presti & Ali H. Ellebedy
Abstract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA)-based vaccines are ~95% effective in preventing coronavirus disease 20191–5. The dynamics of antibody secreting plasmablasts (PBs) and germinal centre (GC) B cells induced by these vaccines in humans remain unclear. We examined antigen-specific B cell responses in peripheral blood (n=41) and draining lymph nodes (LNs) in 14 individuals who received two doses of BNT162b2, an mRNA-based vaccine encoding full-length SARS-CoV-2 spike (S) gene1. Circulating IgG- and IgA-secreting PBs targeting the S protein peaked one week after the second immunization then declined, becoming undetectable three weeks later. These PB responses preceded maximal levels of serum anti-S binding and neutralizing antibodies to an early circulating SARS-CoV-2 strain as well as emerging variants, especially in individuals previously infected with SARS-CoV-2, who produced the most robust serologic responses. By examining fine needle aspirates (FNAs) of draining axillary LNs, we identified GC B cells that bound S protein in all participants sampled after primary immunization. Remarkably, high frequencies of S-binding GC B cells and PBs were sustained in these draining LNs for at least twelve weeks after the booster immunization. S-binding GC B cell-derived monoclonal antibodies predominantly targeted the receptor binding domain of the S protein, with fewer clones binding to the N-terminal domain or to epitopes shared with the S proteins of the human betacoronaviruses OC43 and HKU1. The latter cross-reactive B cell clones had higher levels of somatic hypermutation compared to those that only recognized SARS-CoV-2 S protein, suggesting a memory B cell origin. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent GC B cell response, enabling the generation of robust humoral immunity.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA)-based vaccines are ~95% efective in preventing coronavirus disease 20191–5. The dynamics of antibody secreting plasmablasts (PBs) and germinal centre (GC) B cells induced by these vaccines in humans remain unclear. We examined antigen-specifc B cell responses in peripheral blood (n=41) and draining lymph nodes (LNs) in 14 individuals who received two doses of BNT162b2, an mRNA-based vaccine encoding full-length SARS-CoV-2 spike (S) gene1. Circulating IgG- and IgA-secreting PBs targeting the S protein peaked one week after the second immunization then declined, becoming undetectable three weeks later. These PB responses preceded maximal levels of serum anti-S binding and neutralizing antibodies to an early circulating SARS-CoV-2 strain as well as emerging variants, especially in individuals previously infected with SARS-CoV-2, who produced the most robust serologic responses. By examining fne needle aspirates (FNAs) of draining axillary LNs, we identifed GC B cells that bound S protein in all participants sampled after primary immunization. Remarkably, high frequencies of S-binding GC B cells and PBs were sustained in these draining LNs for at least twelve weeks after the booster immunization. S-binding GC B cell-derived monoclonal antibodies predominantly targeted the receptor binding domain of the S protein, with fewer clones binding to the N-terminal domain or to epitopes shared with the S proteins of the human betacoronaviruses OC43 and HKU1. The latter cross-reactive B cell clones had higher levels of somatic hypermutation compared to those that only recognized SARS-CoV-2 S protein, suggesting a memory B cell origin. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent GC B cell response, enabling the generation of robust humoral immunity.
The concept of using mRNAs as vaccines was introduced over 30 years ago6,7. Key refinements that improved the biological stability and translation capacity of exogenous mRNA enabled development of these molecules as vaccines8,9. The emergence of SARS-CoV-2 in December, 2019 and the ensuing pandemic has unveiled the potential of this platform9–11. Hundreds of millions of people have received one of the two SARS-CoV-2 mRNA-based vaccines that were granted emergency use authorization by the FDA in December, 2020. Both vaccines demonstrated remarkable immunogenicity in phase 1/2 studies and efficacy in phase 3 studies1–4,12–14. Whether these vaccines induce robust and persistent germinal center (GC) reactions that are critical for generating high-affinity and durable antibody responses has not been examined in humans.
To address this question, we conducted an observational study of 41 healthy adults (8 with history of confirmed SARS-CoV-2 infection) who received the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine (BNT162b2) (Extended Data Tables 1, 2). Blood samples were collected at baseline and at weeks 3 (pre-boost), 4, 5, 7, and 15 after the first immunization (Fig. 1a). FNAs of the draining axillary LNs were collected from 14 participants (none with history of SARS-CoV-2 infection) at weeks 3 (pre-boost), 4, 5, 7, and 15 after the first immunization (Fig. 1a).
Antibody-secreting PBs in blood that bound SARS-CoV-2 S protein were measured by enzyme-linked immune absorbent spot (ELISpot) assay. SARS-CoV-2-S-specfic IgG- and IgA-secreting PBs were detected three weeks after primary immunization in 24 of 33 participants with no history of SARS-CoV-2 infection but 0 of 8 participants previously infected with SARS-CoV-2. PBs peaked in blood during the first week after boosting (week 4 after primary immunization), with frequencies varying widely from 3 to 4,100 S-binding PBs per 106 PBMC (Fig. 1b, c).
Plasma IgG antibody titers against S measured by ELISA increased in all participants over time, reaching peak geometric mean half-maximal binding titers (GMBTs) of 5,567 and 15,850 5 weeks after immunization among participants without and with history of SARS-CoV-2 infection, respectively, with a subsequent decline by 15 weeks after immunization. Anti-S IgA titers and IgG titers against the receptor binding domain (RBD) of S showed similar kinetics, reaching peak GMBTs of 172 and 739 for anti-S IgA and 4,501 and 7,965 for anti-RBD IgG among participants without and with history of SARS-CoV-2 infection, respectively before declining. IgM responses were weaker and more transient, peaking 4 weeks after immunization among participants without history of SARS-CoV-2 infection with a GMBT of 78 and were undetectable in all but two previously infected participants (Fig. 1d, Extended Data Fig. 1a).
The functional quality of serum antibody was measured using high-throughput focus reduction neutralization tests15 on Vero-TMPRSS2 cells against three authentic infectious SARS-CoV-2 strains with sequence variations in the S gene16,17: (a) a Washington strain (2019n-CoV/USA) with a prevailing D614G substitution (WA1/2020 D614G); (b) a B.1.1.7 isolate with signature changes in the spike gene18, including the 69–70 and 144–145 deletions and N501Y, A570D, D614G and P681H substitutions; and (c) a chimeric SARS-CoV-2 with a B.1.351 spike gene in the Washington strain background (Wash B.1.351) that contained the following changes: D80A, 242-244 deletion, R246I, K417N, E484K, N501Y, D614G and A701V. Serum neutralizing titers increased markedly in participants without history of SARS-CoV-2 infection following boosting, with geometric mean neutralization titers (GMNTs) against WA1/2020 D614G of 58 three weeks after primary immunization and 572 two or four weeks after boost (five or seven weeks after primary immunization). Neutralizing titers against B.1.1.7 and B.1.351 variants were lower, with GMNTs of 49 and 373 against B.1.1.7 and 36 and 137 against B.1.351 after primary and secondary immunization, respectively. In participants with a history of prior SARS-CoV-2 infection, neutralizing titers against all three viruses were detected at baseline (GMNTs of 241.8, 201.8, and 136.7 against WA1/2020 D614G, B.1.1.7, and B.1.351 respectively). In these participants, neutralizing titers increased more rapidly and to higher levels after immunization, with GMNTs of 4,544, 3,584, and 1,897 against WA1/2020 D614G, B.1.1.7, and B.1.351, respectively after primary immunization, and 9,381, 9,351, and 2,749 against WA1/2020 D614G, B.1.1.7, and B.1.351 respectively after secondary immunization. These GMNTs were 78-, 73-, and 53-fold higher after primary immunization and 16-, 25-, and 20-fold higher after boosting against WA1/2020 D614G, B.1.1.7, and B.1.351, respectively than participants without history of SARS-CoV-2 infection. (Extended Data Fig. 1b).
The BNT162b2 vaccine is injected into the deltoid muscle, which drains primarily to the lateral axillary LNs. Ultrasonography was used to identify and guide FNA of accessible axillary nodes on the side of immunization approximately 3 weeks after primary immunization. In 5 of the 14 participants, a second draining LN was identified and sampled following secondary immunization (Fig. 2a). GC B cells, defined as CD19+ CD3– IgDlo Bcl6+ CD38int lymphocytes, were detected in all LNs (Fig. 2b, d, Extended Data Fig. 2a, Extended Data Table 3). FNA samples were co-stained with two fluorescently labeled S probes to detect S-binding GC B cells. A control tonsillectomy sample with a high frequency of GC B cells collected prior to the SARS-CoV-2 pandemic from an unrelated donor was stained as a negative control. S-binding GC B cells were detected in FNAs from all 14 participants following primary immunization. The kinetics of the GC response varied among participants, but S-binding GC B cell frequencies increased at least transiently in all participants after boosting and persisted at high frequency in most individuals for at least 7 weeks. Notably, S-binding GC B cells remained at or near their peak frequency 15 weeks after immunization in 8 of the 10 participants sampled at that time point, and these prolonged GC responses had high proportions of S-binding cells (Fig. 2c–e, Extended Data Fig. 2b).
To evaluate the domains targeted by the S protein-specific GC response after vaccination, we generated recombinant monoclonal antibodies (mAbs) from single-cell sorted S-binding GC B cells (defined by the surface marker phenotype CD19+ CD3– IgDlo CD20hi CD38int CD71+ CXCR5+ lymphocytes) from three of the participants one week after boosting (Extended Data Fig. 2a). Fifteen, five, and seventeen S-binding, clonally distinct mAbs were generated from participants 07, 20 (LN 1), and 22, respectively (Extended Data Table 4). Of the 37 S-binding mAbs, 17 bound RBD, 6 recognized the N-terminal domain, and 3 were cross-reactive with spike proteins from seasonal betacoronavirus OC43; 2 of these mAbs also bound spike from seasonal betacoronavirus HKU1 (Fig. 3a). Clonal relatives of 14 of 15, 1 of 5, and 12 of 17 of the S-binding mAbs were identified among bulk-sorted total PBs from PBMCs and GC B cells 4 weeks after immunization from participants 07, 20, and 22, respectively (Fig. 3b, Extended Data Figs. 2c, 3a, b, and Extended Data Tables 5, 6). Clones related to S-binding mAbs had significantly increased mutation frequencies in their immunoglobulin heavy chain variable region (IGHV) genes compared to previously published naïve B cells, particularly those related to mAbs that cross-reacted with seasonal betacoronaviruses (Fig. 3c, d).