With the controversy surrounding the dosing interval for the Oxford Astra-Zeneca vaccine against coronavirus disease 2019 (COVID-19), a new preprint published on the pre-print server medRxiv* discusses the results of a study of antibody responses to the first and second dose of two currently available SARS-CoV-2 vaccines, Pfizer and Oxford.
These vaccines, also called BNT162b2 and ChAdOx1 nCoV-19, are built on a messenger ribonucleic acid (mRNA) and a non-replicating adenovirus-vectored vaccine platform, respectively. Both are based on the spike protein of the virus, containing the receptor-binding domain (RBD), which is targeted by neutralizing antibodies.
Neutralizing antibodies are responsible for the inhibition of binding between the virus and the host cell receptor, the angiotensin-converting enzyme 2 (ACE2). The detection of anti-nucleocapsid antibodies, raised against the most abundant and among the most immunogenic of the viral antigens, allows vaccine-induced seroconversion to be distinguished from antibodies elicited by natural infection.
COVID-19 Vaccine. Image Credit: M-Foto/Shutterstock.com
The reason for this study
Both vaccines were found to have high efficacy against the SARS-CoV-2, in terms of preventing both infections and symptomatic disease. Evidence is accumulating that they also prevent transmission to a significant extent. Data on immunogenicity has come in mostly from younger and healthier people who have received two doses of the vaccine, according to the manufacturer’s recommendations.
However, the UK first rolled out vaccines with two doses separated by 3-4 weeks. This interval was then extended to 8-12 weeks, to allow as many people as possible to receive at least one dose and the associated degree of immunity. However, the immune response to doses separated by 4-12 weeks remains an area relatively unknown, especially for the Pfizer vaccine.
Again, the immunogenicity of the vaccine among older people and those with comorbidities, such as diabetes, cardiovascular disease, and hypertension, as well as people from Black or Asian backgrounds, needs to be evaluated as these groups are at higher risk of disease and death from COVID-19.
The current study used data from a large community-based study, called Virus Watch, thus ensuring a wide range of subjects with different medical histories. Moreover, both vaccines were included, as well as different dosing intervals.
What were the findings?
The findings indicate that most vaccine recipients show seroconversion to the virus spike antigen by four weeks from the first dose of either vaccine, though earlier with the Pfizer vaccine. However, at four weeks, both show equivalent efficacy in terms of the proportion of seroconverted individuals in both groups (96%) and spike antibody titers at eight weeks.
The slightly lower seroconversion rates compared to the 97% and 99% rates reported at 14 or more days from one dose of the Oxford and Pfizer vaccines could be due to the heterogeneous nature of this cohort, including both those who are older and those with other illnesses.
The REACT2 study showed only 84% seroconversion after a single dose of the Pfizer vaccine, perhaps due to the use of a different assay. Modeling studies corroborate the findings of the current study.
At seven days after the second dose, both vaccines produced 99% seroconversion and high spike antibody levels, at ≥250 U/ml in most cases.
Lower seroconversion in some groups
Immunocompromised individuals show the lowest rates of seroconversion than others. Seroconversion occurred in 86% of the former vs 97% of the latter. Specifically, only a third of organ transplant recipients seroconverted, and a little over half of the radiotherapy recipients.
Over 83% of those on steroids or other immunosuppressants, including cancer chemotherapy and targeted therapy, were seropositive at 28 or more days from the first dose. Surprisingly, after two doses, most people were seropositive (95%-100%), though this dropped to 80% in those with blood cancers.
Lower antibody titers in some groups
The Pfizer vaccine elicited a median titer of 41 U/mL at 28 days as well as 42 days, compared to 30 and 35 U/mL with the Oxford vaccine at these time points. However, no difference could be observed at 56 days or beyond.
Along with diabetes and cardiovascular disease, suppressed immunity is also the most significant risk factor for lower spike antibody titers after the first dose.
Older adults (≥80 years) have lower antibody titers (26 U/mL) compared to 63 U/mL in those aged 18-34 years. This disparity has been suggested by earlier data. However, this does not have an obvious clinical impact in terms of the number of severe infections or death. This could be because even at baseline, older people are already at higher risk for poor outcomes.
Thus, the immunologic measurements indicating protective efficacy should be selected based on the actual outcome that is visualized, since some are more prone to age-dependent differences than others.
Females aged 65-79 years had a median titer of 43 U/mL vs 30 in males at 28 days or more from the first dose. Titers were also lower after one dose in those with other illnesses.
The decrease in vaccine efficacy in those with blood cancers, and, after one dose, in organ transplant recipients, indicates the need to look into further parameters of efficacy and immunogenicity for these groups. Such patients may need an earlier second dose, especially if spike antibodies really correspond to protection against infection.
Supporting data from earlier studies
UK data indicates that one dose of ChAdOx1 or BNT162b2 reduces the risk of infection by 64% and 78%, respectively, from the 21st day onwards. Reduced viral loads are also found from 12 days after one dose, which is thought to correspond to lower infectious potential.
Israeli data pushes back the onset of protection with the Pfizer vaccine to 14 days after the first dose, against both asymptomatic and symptomatic infection, at 52% and 66% protection from day 21 onwards. Significant protection, at 57%, is seen against symptomatic infection from 14 days onwards.
What are the implications?
Interestingly, the immunologic findings in the current study do not reflect real-life differences in vaccine efficacies between the two vaccines at 2-8 weeks.
Differences may be masked by the uncertainty in the available VE estimates, or it may be that, beyond a certain threshold that both vaccines achieve early on, S-antibody levels do not exactly correlate with protection.”
This could be because T lymphocytes come into play even while the spike antibody responses to ChAdOx1 are lower than BNT162b2, and this is responsible for the observed comparable efficacies of both vaccines.
Similarly, the reduced activation of T helper lymphocytes could be partly responsible, at least, for the poor antibody response following vaccination of immunocompromised individuals. Thus, the best correlate of protection may be a combined measure of cellular as well as humoral immunity.
Work in this area will help better understand how vaccine-induced immunity occurs, and the immune phenomena underlying vaccine breakthroughs, using more detailed phenotypic assays of immune cells.
Observed disparities in antibody levels after the first dose by vaccine type, age, and comorbidities highlight the importance of ongoing non-pharmaceutical preventative measures such as social distancing, for partially vaccinated adults, particularly those who are older and more clinically vulnerable.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Shrotri, M. et al. (2021). Spike-antibody responses following first and second doses of ChAdOx1 and BNT162b2 vaccines by age, gender, and clinical factors - a prospective community cohort study (Virus Watch). medRxiv preprint. doi: https://doi.org/10.1101/2021.05.12.21257102. https://www.medrxiv.org/content/10.1101/2021.05.12.21257102v1