CVR - Coronavirus Vaccines R&D Roadmap

Milestone
2.5.a

Vaccine and infection response

In progress

Clarify the interaction between preexisting immunity to coronaviruses and subsequent response to infection and vaccination, such as by evaluating immune kinetics, breadth of protection, the role of epitope masking, and the role of immune memory.

Progress Highlights

Wu 2026 found that severe COVID-19 was associated with quantitatively stronger cross-sarbecovirus antibody responses than mild infection; severe convalescents had broader S1 binding and significantly higher neutralization titers against six animal-derived sarbecoviruses, although the number of viruses neutralized (the overall neutralization breadth) was not significantly different between severity groups.

The majority of studies suggest that anti-RBD IgG antibodies elicited by endemic HCoVs do not provide meaningful cross-protection against SARS-CoV-2 infection in exposed individuals.

Some studies have shown that with higher pre-infection antibody levels to endemic HCoVs (such as HKU1, OC43, NL63, and 229E) developed stronger SARS-CoV-2 antibody responses upon infection, and that SARS-CoV-2 antibodies may cross-react with other coronaviruses, such as OC43.

Lilly 2026 Found that repeated exposure to genetically distinct SARS-CoV-2 antigens can mature B cell responses toward highly conserved sarbecovirus epitopes.

Majdoubi 2026 showed that HKU1 specific b-cell antibodies expanded substantially after SARS-CoV-2 vaccination, especially the first dose, and that these imprinted HKU1 antibodies cross-reacted with conserved SARS-CoV-2 S2 epitopes (with subsequent doses shifting the response more toward S1 epitopes). Higher baseline HKU1 spike IgG levels were associated with lower SARS-CoV-2 infection risk, but higher risk of PASC.

Bean 2025 and Sagar 2021 showed that recent HCoV infection was associated with less-severe COVID, andthat this protection was correlated higher levels of Fc receptor (FcR)-binding antibodies against eCoV spikes and SARS-CoV-2 S2.

Beaudoin-Bussières 2025 notes that SARS-CoV-2 mRNA vaccines have been shown to elicit cross reactive antibodies to multiple SARS-CoV-2 variants and SARS-CoV-1.

Patel 2025 found that in a cohort of 87 patients with recent SARS-CoV-2 infection and variable vaccination history, binding titres for the S2 region of the spike protein, though generally lower than for the S1 region, conferred the greater breadth of protection against emerging variants and even more distantly related coronaviruses. 

Bean 2024 demonstrated that prior SARS-CoV-2 infection (but not vaccination alone) was associated with a lower incidence of symptomatic infections from endemic HCoVs. The cross-protective effect appears to be CD8+ T cell-mediated.

Kim 2024 determined that prior exposure to MERS-CoV boosted immune responses to SARS-CoV-2 vaccination, leading to higher antibody levels in MERS-recovered individuals compared to non-exposed controls.

Morrow 2024 found that, in children from metropolitan Cincinnati, previous exposure to endemic coronaviruses induced strong homotypic immunity, but did not provide protection against other coronaviruses, including SARS-CoV-2.

Santos Alves 2024 found that prior exposure to HCoVs eliciting more rapid immune responses to vaccination may be due to an accelerated recall response mediated by memory B and T cells.

Vilela 2024 found that individuals with pre-existing endemic HCoV immunity exhibited a more rapid induction of SARS-CoV-2-specific antibodies following mRNA vaccination, but that their immune responses were biased towards conserved epitopes, limiting efficacy. 

Painter 2023 showed that prior SARS-CoV-2 vaccination has been demonstrated to enhance early activation of memory T cells and improve immune responses during breakthrough infections.

Soni 2023 found that T-cell responses against SARS-CoV-2 and common HCoVs were reciprocal in some cases but non-reciprocal in others.

Preexisting antibodies can suppress the activation of naïve B cells, leading to a preferential recall of memory B cells that target previously recognized viral epitopes.

Multiple studies have shown that individuals previously vaccinated or infected by early SARS-CoV-2 show reduced ability to generate variant-specific antibodies, with immune imprinting restricting the antibody response to earlier viral epitopes.

Selva 2026 found that IgG4 appears to be more associated with imprinting than other IgG subtypes, with higher % IgG4 composition correlated with reduced Fc receptor engagement.

Bisset 2026 found that heterologous intranasal (IN) boosting may overcome imprinting better than systemic boosting.

Vaccination with multivalent vaccines and repetitive dosing may alleviate imprinting, but the benefit may be temporary.

 

Individuals who have been both infected by and vaccinated against SARS-CoV-2 exhibit broader and more durable immune memory than vaccination alone.

This includes:

Higher magnitude of recall responses (pre-activation of memory B and T cells)

Increased breadth of protection (greater number of recognized epitopes), including against other sarbecoviruses

Greater polyfunctionality of T-cell responses (production of multiple effective cytokine types simultaneously)

Stronger and more durable IgG responses

Alleviation of immune imprinting

Mucosal boosting of individuals that have been previously vaccinated intramuscularly may serve to mimic the protection gained by hybrid immunity.

Fiore-Gartland 2026 found that mRNA vaccination produces stronger neutralizing antibody responses and broader spike-specific TCR responses than mild or asymptomatic infection alone.

Halfmann 2026 found that MERS-CoV vaccination targeting conserved RBD-SD1 proteins elicits cross-reactive binding antibodies across merbecoviruses, but that this effect doesn’t necessarily provide cross-protection due to a lack of inhibition of dPP4 engagement.

In humans, SARS-CoV-1 survivors who received SARS-CoV-2 vaccines, including Pfizer’s mRNA and Ad5-nCoV, exhibited broad neutralization of SARS-CoV-1, SARS-CoV-2 variants, and even animal sarbecoviruses, driven by recall of conserved epitope-targeting immune memory.

SARS-CoV-2 vaccination alone in naïve individuals elicited little to no neutralization of SARS-CoV-1, although hybrid immunity modestly enhanced SARS-CoV-1 cross-neutralization, primarily through antibodies targeting conserved, non-ACE2 binding regions.

Naghibosadat 2025 observed low-level cross-protection against NL63 and OC43 following adenovirus-vectored SARS-CoV-2 vaccination.  

Tang 2025 observed limited in vitro cross-reactivity with endemic coronaviruses like HCoV-NL63 after Moderna vaccination, though this did not translate to boosted antibody titers. 

Alosaimi 2024 found that MERS-CoV survivors showed cross-reactive IgG antibodies capable of binding SARS-CoV-2 spike protein. These antibodies could functionally inhibit ACE2 binding by SARS-CoV-2 RBD, especially in vaccinated individuals. They also found that MERS-CoV survivors who received two doses of SARS-CoV-2 mRNA vaccine had increased anti-MERS-CoV IgG, stronger neutralization against SARS-CoV-2 variants (WT, Delta, BA.5)l, and more potent CD4+ and CD8+ memory T cell responses. 

Dangi 2021 found that vaccination with a SARS-CoV-1 spike-based vaccine in mice conferred cross-neutralizing antibodies and significantly reduced SARS-CoV-2 lung viral loads, indicating that targeting conserved spike regions can provide cross-protection.