Despite the success of COVID-19 vaccination programs in reducing morbidity and mortality, a substantial number of individuals in the general population respond poorly to SARS-CoV-2 vaccination.
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Higher vaccination rates predict reduction in SARS-CoV-2 transmission across the United States.
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- Nadesalingam A
- Cantoni D
- Wells DA
- et al.
Paucity and discordance of neutralizing antibody responses to SARS-CoV-2 VOCs in vaccinated immunodeficient patients and health-care workers in the UK.
Furthermore, only about 20% of individuals throughout low-income countries have received their first dose of the SARS-CoV-2 vaccine.
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- Richie H
- Mathieu E
- Rodés-Guirao L
- et al.
Coronavirus Pandemic (COVID-19).
Neutralising antibodies are a key correlate to protection from COVID-19, with booster vaccines offered to increase protection from new variants.
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- Cantoni D
- Mayora-Neto M
- Nadesalingham A
- et al.
Neutralisation hierarchy of SARS-CoV-2 variants of concern using standardised, quantitative neutralisation assays reveals a correlation with disease severity; towards deciphering protective antibody thresholds.
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- Khoury DS
- Cromer D
- Reynaldi A
- et al.
Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.
However, poor responsiveness to immunisation increases the risk of infection and disease.
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- Singson JRC
- Kirley PD
- Pham H
- et al.
Factors associated with severe outcomes among immunocompromised adults hospitalized for COVID-19—COVID-NET, 10 States, March 2020-February 2022.
The CDC
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- Singson JRC
- Kirley PD
- Pham H
- et al.
Factors associated with severe outcomes among immunocompromised adults hospitalized for COVID-19—COVID-NET, 10 States, March 2020-February 2022.
reported that patients with compromised immune systems accounted for about 12% of adult COVID-19 hospital admissions and had higher rates of intensive care admissions and in-hospital deaths compared with non-immunocompromised inpatients, in both vaccinated and unvaccinated populations. Although a heterogeneous group, the majority of patients with immunodeficiency show variable and weaker antibody-mediated responses post-vaccination to SARS-CoV-2 individuals than without immunodeficiency.
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- Shields AM
- Faustini SE
- Hill HJ
- et al.
SARS-CoV-2 vaccine responses in individuals with antibody deficiency: findings from the COV-AD study.
In March, 2022, a UK report revealed 45 5% of immunocompromised individuals received a booster vaccination dose.
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UK Health Security Agency
COVID-19 Vaccine Surveillance Report Week 11.
However, without immune monitoring it remains unclear which individuals within this high-risk population have sufficient immunity.
Within the variants of concern, the omicron sublineages have represented the predominant variants of concern since December, 2021. Despite lower omicron-related fatality in the vaccinated population than in the unvaccinated population, there remains a significant risk of increased moderate-to-severe disease in individuals with partial or no immunity. WHO has recognised five different omicron lineages. Alongside mutations found in BA.1 and BA.2, the latest BA.4 and BA.5 variants have mutations that enhance antibody escape to the point of successful reinfection in immunocompetent, vaccinated individuals with previous BA.1 or BA.2 infection.
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- Pulliam JRC
- van Schalkwyk C
- Govender N
- et al.
Increased risk of SARS-CoV-2 reinfection associated with emergence of omicron in South Africa.
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- Cao Y
- Yisimai A
- Jian F
- et al.
BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by omicron infection.
Countries such as the UK offered an initial two-dose regimen of either ChAdOx nCoV-19 or BNT162b2 and a third mRNA-based SARS-CoV-2 booster dose, including Moderna’s Spikevax. To determine the breadth of antibody-mediated neutralisation in serum samples from both healthy individuals (ie, health-care workers) and patients with immunodeficiencies in the UK after second-dose immunisation, we used pseudotyped virus incorporating either the BA.1, BA. 2, or BA.2.12.1 spike, or the shared BA.4 and BA.5 spike. In the 4–6 weeks after the second dose of vaccination, neutralizing immune responses to the ancestral (vaccine) strain were detected in 97% of the healthy cohort, with a median neutralizing IC
50 titre of 956 (appendix p1). In comparison, detectable responses were found in only 44% of the healthy cohort after the first dose of vaccination, which we reported in 2021.
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- Nadesalingam A
- Cantoni D
- Wells DA
- et al.
Paucity and discordance of neutralizing antibody responses to SARS-CoV-2 VOCs in vaccinated immunodeficient patients and health-care workers in the UK.
Compared to the ancestral strain, fewer health-care workers mounted a detectable neutralising response to any of the omicron strains after two doses and, of those who responded, neutralizing IC50 titres were significantly lower than titres against the ancestral strain (appendix p 1), although increased relative to responses following first vaccination doses (Wilcoxon matched-pairs test, p
After a third vaccination dose (BNT162b2 or Spikevax) in health-care workers, the breadth of serum neutralizing activity to omicron variants of concern was eight-times higher in median IC50 against BA.2.12.1 and 14-times higher in median IC50 against the shared BA.4 and BA.5 spike than after the second vaccination dose (Mann-Whitney, pappendix p 1). However, there still remain healthy individuals with no or low detectable neutralising responses after the third vaccination dose (appendix p 1). Some individuals had a primary infection (presumed omicron BA.1 or BA.2 due to local temporal epidemiology) after receiving three doses of vaccination. Notably these individuals, infected during the BA.1 and BA.2 waves, had significantly higher neutralizing titres against the currently circulating BA.2.12.1 and BA.4 and BA.5 omicron variants than individuals who were not infected after the third vaccination dose (Mann Whitney, pappendix p 1).
Although healthy individuals seem to show a neutralizing capacity for omicron that progressively increases with subsequent booster immunisations (and infection), individuals with immunodeficiencies responded quite differently. Whereas neutralizing IC
50 in patients with immunodeficiencies was higher against the ancestral strain after second-dose vaccination than after first-dose vaccination,
2
- Nadesalingam A
- Cantoni D
- Wells DA
- et al.
Paucity and discordance of neutralizing antibody responses to SARS-CoV-2 VOCs in vaccinated immunodeficient patients and health-care workers in the UK.
the majority did not neutralise any of the omicron variants (appendix p 1). After two immunisations, only 18% of patients with immunodeficiencies neutralised BA.1, 22% neutralised BA.2, 17% neutralised BA.2.12.1, and 17% neutralised BA.4 and BA.5 (appendix p 1). Within the patients with immunodeficiencies who did respond to omicron, neutralizing IC50 titres increased between first-dose
2
- Nadesalingam A
- Cantoni D
- Wells DA
- et al.
Paucity and discordance of neutralizing antibody responses to SARS-CoV-2 VOCs in vaccinated immunodeficient patients and health-care workers in the UK.
and second-dose vaccination against both BA.1 and BA.2 (Wilcoxon matched-pairs test; p50 titres after the third vaccination dose (Mann-Whitney, p=0·07 and p=0·27, respectively).
In summary, healthy individuals in the UK benefited from boosting with a third ancestral-strain-based vaccine and it diversified their neutralizing responses against BA.2·12·1 and BA.4 and BA.5. However, individuals with immunodeficiencies mounted weak responses against omicron, which were not significantly boosted. Individuals with different underlying immunodeficiencies will benefit from next-generation vaccines containing more antigenic targets with a broad variant-targeting capacity. This suggests that this group should be prioritised for the receipt of a variant-informed SARS-CoV-2 vaccines containing relevant mutations specific to the variants of concern.
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