ABSTRACT
Knowledge of the factors contributing to the development of protective immunity after vaccination with COVID-19 mRNA vaccines is fragmentary. Thus we employed high-temporal-resolution transcriptome profiling and in-depth characterization of antibody production approaches to investigate responses to COVID-19 mRNA vaccination. There were marked differences in the timing and amplitude of the responses to the priming and booster doses. Notably, two distinct interferon signatures were identified, that differed based on their temporal patterns of induction. The first signature (S1), which was preferentially induced by type I interferon, peaked at day 2 post-prime and at day 1 post-boost, and in both instances was associated with subsequent development of the antibody response. In contrast, the second interferon signature (S2) peaked at day 1 both post-prime and post-boost but was found to be potently induced only post-boost, where it coincided with a robust inflammation peak. Notably, we also observed post-prime-like (S1++,S20/+) and post-boost-like (S1++,S2++) patterns of interferon response among COVID-19 patients. A post-boost-like signature was observed in most severely ill patients at admission to the intensive care unit and was associated with a shorter hospital stay. Interestingly, severely ill patients who stayed hospitalized the longest showed a peculiar pattern of interferon induction (S1-/0,S2+), that we did not observe following the administration of mRNA vaccines. In summary, high temporal resolution profiling revealed an elaborate array of immune responses elicited by priming and booster doses of COVID-19 mRNA vaccines. Furthermore, it contributed to the identification of distinct interferon-response phenotypes underpinning vaccine immunogenicity and the course of COVID-19 disease.
Subject(s)
COVID-19 , Inflammation , Severe Acute Respiratory SyndromeABSTRACT
Next-generation vaccines that are safe, effective and with equitable access globally are required to prevent SARS-CoV-2 transmission at a population level. One strategy that has gained significant interest is to repurpose existing licensed vaccines for use against COVID-19. In this report, we have exploited the immunostimulatory properties of bacille Calmette-Guerin (BCG), the vaccine for tuberculosis, to develop a SARS-CoV-2-specific and highly immunogenic vaccine candidate. Combination of BCG with a stabilized, trimeric form of the SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the sera of vaccinated mice, which could be further augmented by the addition of alum. This vaccine formulation, termed BCG:CoVac, induced a Th1-biased response both in terms of IgG antibody subclass and cytokine release by vaccine-specific CD4+ and CD8+ T cells. A single dose of BCG:CoVac was sufficient to induce high-titre SARS-CoV-2 neutralizing antibodies (NAbs) that were detectable as early as 2 weeks post-vaccination; NAb levels were greater than that seen in the sera of SARS-CoV-2-infected individuals. Boosting of BCG:CoVac-primed mice with a heterologous vaccine combination (spike protein plus alum) could further increase SARS-CoV-2 spike protein-specific antibody response. BCG:CoVac would be broadly applicable for all populations susceptible to SARS-CoV-2 infection and in particular could be readily incorporated into current vaccine schedules in countries where BCG is currently used. ImportanceEffective distribution of vaccine to low- and middle-income countries is critical for the control of the COVID-19 pandemic. To achieve this, vaccines must offer effective protective immunity yet should be cheap to manufacture and meet cold chain management requirements. This study describes a unique COVID-19 vaccine candidate, termed BCG:CoVac, that when delivered as a single dose induces potent SARS-CoV-2 specific immunity in mice, particularly through generation of high-titre, anti-viral neutralising antibodies. BCG:CoVac is built on safe and well-characterised vaccine components: 1) the BCG vaccine, used for control of tuberculosis since 1921 which also has remarkable off target effects, protecting children and the elderly against diverse respiratory viral infections; 2) Alhydrogel adjuvant (Alum), a low cost, globally accessible vaccine adjuvant with an excellent safety record in humans (part of >20 licensed human vaccines and in use >70 years); 3) Stabilized, trimeric SARS-CoV-2 spike protein, which stimulates immune specificity for COVID-19. Further assessment in humans will determine if BCG:CoVac can impart protective immunity against not only SARS-CoV-2, but also other respiratory infections where BCG has known efficacy.