Background
A growing number of vaccines have been approved (conditional marketing approval) and are being rolled out worldwide. These preventive vaccines stimulate the two components of the immune system: the humoral immunity (i.e. the production of antibodies) and the cellular immunity.
The EMA approved base-vaccination schemes include vaccines based on mRNA (2 doses for the vaccines of Pfizer–BioNTech and Moderna) or based on an adenovector (2 doses of Astra-Zeneca or 1 dose of Johnson & Johnson/Janssen).
What is the effectiveness of vaccination and what are breakthrough infections?
In the large scale phase 3 randomized trials, each of the available vaccines reduced the probability of infection (and the associated risk of transmission) with at least 50%, the minimum criterion for marketing authorization. In addition, the vaccines reduce even more the risk of infection with severe disease and death (reduction of about 90%). Randomized direct comparisons of the clinical effectiveness of the vaccines are still missing.
The level of neutralizing antibodies against the circulating variants are higher after mRNA vaccines than after adenovector-based vaccines. All vaccines frequently cause transient and mild side-effects. This also the case if a different vaccine is used as a second dose (off-label).
The available data after administration of an extra dose of mRNA vaccine in risk groups do not suggest any major difference in side-effect profile. Serious side-effects caused by vaccination occur very rarely. These differ for adenovector vaccines (e.g. thrombosis with low levels of platelets) and mRNA vaccines (e.g. myocarditis and pericarditis).
An infection after a full base-vaccination scheme (minimum 1-4 weeks after the last dose) is called a breakthrough infection. The definition used however varies between different publications, which hampers comparisons across studies.
Which variables can have an impact on the effectiveness of vaccination?
- The vaccine(s) itself, the route of administration, the dose, the storage conditions, the scheme of administration and the time period after vaccination, given a possible decrease of the protection over time (“waning”)
- The person and the immune system, age and gender, a history of Covid-19 with a specific variant, and diseases or treatments that compromise the immune response (“immunocompromised patients”)
- The virus variant and the quantity of virus the person is exposed to.
A number of the variables we can control. The quantity of virus we are exposed to can be reduced using e.g. ventilation, physical distancing and masks.
Another possibility consists of an adaptation of the vaccination schemes in the short term using an extra/booster dose of a (mRNA) vaccine. EMA did not yet approve any vaccine for such booster vaccination. This mean such use is still considered off-label. Vaccines based on another variant of the virus are in development but not yet approved.
A booster dose is typically administered at least 6 months after the base vaccination. In the published studies of an extra mRNA dose, this dose was sometimes already administered two months after base-vaccination (note: this is called ‘extra dose’ in the present report). It is more of an extension of a base vaccination scheme without counting on a real booster effect. These results have also been considered in this report.
Possible endpoints of effectiveness of an extra/booster dose of mRNA vaccine
For the evaluation of effectiveness a distinction is to be made between protection against infection and transmission (‘sterile immunity’) and protection against severe Covid-19 disease. It has been suggested that the optimal vaccination strategy might differ for these two aims. An extra/booster dose of mRNA is likely to increase the quantity of virus-neutralizing antibodies and this may decrease breakthrough infections and further transmission, at least of those variants being bound sufficiently.
For the protection against severe Covid-19 caused by the new variants a broad cellular immunity might be important. In theory, those who were vaccinated after a history of a natural infection have a broader base as protection compared with those who never had an infection.
“Finally, timing a boost for optimal responses will depend on whether the objective is to prevent viral acquisition or disease. Given the rapid emergence of variants, in the former, boosting would be needed on a far shorter time scale than the latter. The optimal timing for boosting to prevent serious disease will depend on the stability and further evolution of the memory B cell compartment.” https://www.biorxiv.org/content/10.1101/2021.07.29.454333v1
Effectiveness trials after an extra/booster mRNA dose are still missing to confirm or refute these theoretical considerations.
Use of a correlate of protection?
There is growing evidence that a breakthrough infection with a specific variant after vaccination in immunocompromised patients1, and healthy individuals2 is associated with absence of the pre- exposure virus-blocking antibody levels (as a first step towards a correlate of protection). Earle et al. described a robust correlation between neutralizing titre and efficacy (ρ= 0.79) and binding antibody titre and efficacy (ρ= 0.93).3
The measure of a specific cellular immune response is more complex compared with the assessment of specific antibody levels. But also the minimum level of detection as well as the reported level of antibodies and its specificity (anti-Spike (S), anti-RBD IgG) depend on the assay used. A standardized assay of virus-blocking antibody levels could potentially identify subjects in need of an extra/booster dose. The WHO International Standard (IS) for anti-SARS-CoV-2 antibody allows for assay unit conversion to international units. This facilitates the comparison of datasets and the further research for a correlate of protection. https://www.who.int/publications/m/item/WHO-BS-2020.2403
A single immune response cut-off value by variant which would protect an individual against mild or severe Covid-19 has not yet been determined. Therefore this test-and-boost approach (as in use for hepatitis B in healthcare workers) has been proposed but is still under research for SARS-CoV-2 and not yet ready for routine implementation.
On duration of protection after vaccination
According to Barclay4: “It is highly likely that vaccine induced immunity to SARS-CoV-2 infection, and potentially severe disease (but probably to a lesser extent) will wane over time. This is likely to be first detected by vaccine failures in vulnerable cohorts (for example a high rate of infections in people vaccinated over time, including hospitalized cases). It is therefore likely that there will be vaccination campaigns against SARS-CoV-2 for many years to come, but currently we do not know what will be the optimal required frequency for re-vaccination to protect the vulnerable from COVID disease.”
Shrotri et al. showed a significant trend of declining Spike (S)-antibody levels for both ChAdOx1 and BNT162b2, with levels reducing by about five-fold for ChAdOx1, and by about two-fold for BNT162b2, between 21–41 days and 70 days or more after the second dose.5 Results were consistent for sex, age, and clinical vulnerability.
For BNT162b2, S-antibody levels reduced from a median of 7 506 U/mL (IQR 4 925–11 950) at 21–41 days, to 3 320 U/mL (1 566–4 433) at 70 or more days. For ChAdOx1, S-antibody levels reduced from a median of 1201 U/mL (IQR 609–1 865) at 0–20 days to 190 U/mL (67–644) at 70 or more days.
Thomas et al. (pre-print) describes a vaccine efficacy (VE) of BNT162b2 against lab confirmed COVID-19 cases of 91% (95% CI 89.0-93.2) through up to 6 months of follow-up, among evaluable participants and irrespective of previous SARS-CoV-2 infection.6
VE of 86%-100% was seen across countries and in populations with diverse characteristics of age, sex, race/ethnicity, and COVID-19 risk factors in participants without evidence of previous SARS-CoV-2 infection. VE against severe disease was 97% (95% CI 80.3−99.9). In South Africa, where the SARS-CoV-2 variant of concern,
B.1.351 (beta), was predominant, 100% (95% CI 53.5, 100.0) VE was observed.
Sampling of germinal centre B cells in 14 individuals who received two doses of BNT162b2 revealed binding of S protein in all participants, demonstrating that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent germinal centre B cell response, which enables the generation of robust humoral immunity.7 High frequencies of S-binding germinal centre B cells and plasmablasts were sustained in these draining lymph nodes for at least 12 weeks (samples between 3 and up to 15 weeks) after the second dose.
Zou et al. studied the SARS-CoV-2-specific T cell immunity at 6 months following primary infection in 100 donors from a multicentre trial (mostly US) with 45 441 participants.8 Predominant CD4+ T cell responses with strong interleukin (IL)-2 cytokine expression were present and median T cell responses were 50% higher in donors who had experienced a symptomatic infection, indicating that the severity of primary infection establishes a ‘set point’ for cellular immunity.
T cell responses to spike and nucleoprotein/membrane proteins were correlated with peak antibody levels. Furthermore, higher levels of nucleoprotein-specific T cells were associated with preservation of nucleoprotein- specific antibody level although no such correlation was observed in relation to spike-specific responses.
In conclusion, our data are reassuring that functional SARS-CoV-2-specific T cell responses are retained at 6 months following infection.
Barouch et al. describe the duration of protection following Ad26.COV2.S vaccination for COVID-19 with a sub-analysis of their Phase 1/2a trail showing results indicating that humoral and cellular immune responses were maintained until at least 8 months after vaccination.9
Results of these laboratory experiments should however be confirmed with effectiveness data.
Effectiveness and safety after three doses of Covid-19 vaccine
As currently no clinical effectiveness data are available, only immune response data are presented in the following paragraphs.
Literature search
On 4 August, 2021, two searches were performed in Pubmed (((covid-19[Title/Abstract] OR SARS- CoV-2[Title/Abstract]) AND (vaccine[Title/Abstract])) AND (boost[Title/Abstract]) – filter: last year; ((((covid-19[Title/Abstract] OR SARS-CoV-2[Title/Abstract]) AND (vaccine[Title/Abstract])))) AND (three AND doses) – filter: last year), which resulted in 116 and 80 hits, respectively. Screening of titles and abstracts resulted in two full text documents which were included in the literature review.32, 55
In addition, a search for pre-publications (https://www.medrxiv.org/; “COVID-19 AND vaccine AND boost” – filter: between 01 May, 2021 and 04 Aug, 2021) yielded 245 hits. After screening of titles and abstracts, two full text documents were identified, which were included in the literature review. 56, 57 Publications in pre-print status at the time of the search are indicated with ‘pre-print’.
Three more publications were identified by the experts.1, 58, 59
A narrative review of the retrieved publications is presented below.
Healthy adults
Interim results are available from a double-blind, randomized, placebo-controlled phase 2 clinical trial in China in which 540 healthy adults (aged 18-59 years) received a third dose of the CoronaVac vaccine (pre-print; Box 1).56
Immune response
The primary outcome was geometric mean titres (GMTs) of neutralizing antibody to live SARS- CoV-2.
In the 3 μg group, neutralizing antibody titres induced by the first two doses declined after 6-8 months to below the seropositive cut-off (Schedule 2: GMT= 4.1 [95%CI 3.3-5.2]; schedule 4: GMT=
6.7 [95%CI 5.2-8.6] for). When a third dose was given 6-8 months after a second dose, GMTs assessed 14 days later increased to 137.9 [95%CI 99.9-190.4] for schedule 2, and 143.1 [95%CI 110.8-184.7] for schedule 4, approximately 3-fold above Schedule 1 and Schedule 3 GMTs after third doses.
In the 6 μg group, similar patterns were observed.
Box 1 – Pan et al., 202156 (pre-print)
- Country: China
- Design: double-blind, randomized, placebo-controlled phase 2 clinical trial (interim results)
- Subjects: 540 healthy adults, aged 18-59 years
- Vaccine: CoronaVac (Dose 1, 2 & 3)
- Schedule(s):
- Schedule 1: days 0, 14, 42; 3 subgroups: medium dose* (n=60), high dose (n=60) and placebo
(n=30) – third dose: n=139
- Schedule 2: days 0, 14, 194; 3 subgroups: medium dose* (n=60), high dose (n=60) and placebo
(n=30) – third dose: n=141
- Schedule 3: days 0, 28, 56; 3 subgroups: medium dose* (n=60), high dose (n=60) and placebo
(n=30) – third dose: n=130
- Schedule 4: days 0, 28, 208; 3 subgroups: medium dose* (n=60), high dose (n=60) and placebo
(n=30) – third dose: n=130
- Follow-up:
- Schedule 1 & 3: six months after third dose
- Schedule 2 & 4: six months after second dose
*Medium dose: 3 μg per 0.5 mL of aluminium hydroxide diluent per dose; high dose: 6 μg per 0.5 mL of aluminium hydroxide diluent per dose
Safety
Participants were required to record injection-site adverse events (e.g., pain, redness, swelling), or systemic adverse events (e.g., allergic reaction, cough, fever) on diary cards within 7 days after the third dose. From days 8-28 after the third dose, unsolicited adverse reactions were collected by spontaneous reporting from participants. Serious adverse events were collected until 6 months after the second dose for schedule 2 and 4 groups, and until 6 months after three doses for schedule 1 and 3 groups.
The severity of solicited local and systemic adverse reactions reported within 28 days after the third dose were grade 1 to grade 2(a) in all vaccination cohorts (Figure 6). The most common reported reaction was injection-site pain. Incidences of adverse reactions after the third dose were 7.91% and 3.08% for schedule 1 and schedule 3; in the 3 μg group, the overall incidence of adverse reactions with 28 days after the third dose was ten (18.18%) of 55 participants in schedule 2 and ten (19.23%) of 52 in schedule 4, which was similar with the highest incidence of adverse reactions for schedule 1 (18.33%) after the first dose) and schedule 3 (18.33% after the first dose). Most adverse reactions were grade 1 in severity. There were no significant differences among the 3 μg, 6 μg, and placebo groups in any of the schedules.
A total of fourteen serious adverse events among nine participants were reported from the beginning of vaccination to 6 months after the second dose for schedule 2 and 4, and to 6 months after the third dose for schedule 1 and 3. None of the serious adverse events were considered by the investigators to be related with vaccination. The authors do not specify after which dose the serious adverse events occurred.
Lymphoid malignancies
In France (Nice), a prospective case series was analysed on 45 patients with lymphoid malignancies, who were given a third dose of Pfizer–BioNTech (pre-print; Box 2).57
Immune response
Among the 43 assessable patients, 18 (n=9 CLL, n=8 NHL, n=1 MM; 41.8%) patients had no anti-S Abs before dose 3 was administered; they all remained negative after dose 3. Fourteen of these 18 patients had already received an anti-CD20 Mab treatment, nine of them within the 12 months preceding the vaccine. One seronegative patient with MM was under active treatment for HIV infection.
Among the 25 patients with positive anti-S titres before dose 3, all patients remained positive and 23 of them increased their anti-S titre after dose 3. Their median anti-S titre increased from 87.1 U/mL [range: 1.2-693] to 3386 U/mL [range: 6.6-20312] (p < 0.001).
Patients with CLL and/or with previous anti-CD20 therapy treated within 12 months of administration of dose 3 had no significant increase of the humoral response. Among 22 available patients (CLL n=10, NHL n=12), dose 3 significantly increased the median IFN-gamma secretion. On eight (36.4%) patients who were double-negative for both immune and cellular response, five (22.7%) patients remained double-negative after dose 3.
Box 2 – Re et al., 202157 (pre-print)
- Country: France (Nice)
- Design: case series
- Subjects: 45 adult patients (median age of 43 patients included in analysis: 77 years [range: 37-92]
- Chronic lymphocytic leukemia (CLL): n=15
- Indolent and aggressive B cell non-Hodgkin lymphoma (NHL): n=14
- Multiple myeloma (MM): n=16
- Vaccine: Pfizer–BioNTech (BNT162b2; Dose 1, 2 & 3)
- Schedule(s): dose 3 given 78 days [range: 47-114] after dose 2* of the same vaccine
Follow-up: not reported
*Not specified when dose 2 was given
Safety
Among the 43 patients no novel adverse events were observed after the third dose.57
Hemodialysis
Another French study assessed the efficacy and safety of a third dose of vaccine BNT162b2 (Pfizer– BioNTech) in maintenance hemodialysis (MHD) patients (Box 3).1 The third dose was administered to 56/66 (84.8%) of MHD patients with suboptimal anti-RBD IgG response and also to 19/40 (47.5%) MHD patients with optimal IgG response. The following patients were excluded from the third dose: diagnosis of COVID-19 within the last 3 months, organ transplantation within the last 3 months, Rituximab injection within the last 3 months, ongoing flare of vasculitis, acute sepsis, major surgery within the last 2 weeks.
Box 3 – Espi et al., 20211 (pre-print)
- Country: France (Lyon)
- Design: case series
- Subjects: 75 patients in maintenance hemodialysis (MHD; 56 with suboptimal anti-RBD IgG response and 19 with optimal IgG response after two doses; mean age: 65.8± 14.4 years)
- Vaccine: Pfizer–BioNTech (BNT162b2; Dose 1, 2 & 3)
- Schedule(s): third dose ‘within 3 months after the second vaccine injection’
- Follow-up: immune response assessed 10 to 14 days after the 3rd vaccine injection; data on adverse events collected within 7 days after 3rd vaccine
Immune response
When the whole cohort of MHD patients (n=75) was considered, a significant increase in the median titre of anti-RBD IgG was observed after the third dose of the vaccine (309.8 [36.5 –996.3] vs. 2 212 [394.9 – 3247]; p<0.0001) binding arbitrary units (BAU)/mL after the second and third dose, respectively. However, this global positive result hides major inter-individual heterogeneity.
The 19 MHD patients with optimal humoral response after the second dose of vaccine, all maintained high levels of anti-RBD IgG after the third dose but without significant increase of their titre (2724 [1812 – 4018] vs 3620 [2212 – 10907] BAU/mL after the second and third dose,respectively; p=0.087;Figure 7).
The remaining 56 MHD patients with suboptimal humoral response after the second dose were divided into two categories: i) those with anti-RBD IgG titre below the threshold of positivity of the assay (dotted line Figure 7A): non responders (n=12), and ii) those with low but detectable levels of anti-RBD IgG: low responders (n=44). In contrast with MHD patients with optimal humoral response after the second dose, both of the suboptimal humoral response subgroups experienced a significant increase of anti-RBD IgG after the third dose: 217.8 [71.2 – 617.9] vs 2281 [441.4 – 2855] BAU/mL (Figure 7C; p<0.0001) for low responders and 0.61 [0.43 – 2.8] vs 31.5 [1.76 – 171.8] BAU/mL (Figure 7D; p=0.0005) for non-responders. However, 29/44 (66%) of low responders but only 1/12 (8%) of non-responders reached optimal titre of anti-RBD IgG (Figure 7C-D; p= 0.0006). In fact, half of non- responders after the second dose of vaccine remained without detectable anti-RBD IgG after dose three (6/12, 50%; Figure 4D), while the rest (5/12, 42%; Figure 7D) did develop anti-RBD IgG but at suboptimal titres.
Immune effectors directed against the spike protein of SARS-Cov-2 were quantified in 30 healthy volunteers (open triangles) after second vaccine dose and in 75 MHD patients (open circles) after the second and third dose; A-D/ Anti RBD-IgG titres expressed in binding arbitrary units (BAU/mL). Upper dashed line represents the lowest value observed in healthy volunteers after the standard (2 doses) scheme of vaccination and define the threshold for optimal response. MHD patients with sub-optimal response after the second dose of vaccine were further divided into non-responders and low responders, depending whether anti RBD-IgG titre was respectively below or above the threshold of positivity (dotted line) of the assay (Figure 7A). Evolution of anti RBD-IgG titres between the second and third dose of vaccine were compared in optimal responders (n=19, Figure 7B), low responders (n=44, Figure 7C) and non-responders (n=12, Figure 7D). Wilcoxon test.
The T cell responses of MHD patients after the second dose was much more heterogeneous than that of healthy volunteers (Figure 8). The third dose of vaccine did not result in a significant increase in spike-specific CD4+ T cells in the circulation of MHD patients, neither when the amount of IFN gamma (0.101 [0.016 – 0.856] vs. 0.269 [0.030 – 0.825] I.U/mL; p=0.817) nor when the proportion of MHD patients with detectable spike-specific CD4+ T cells (57% vs. 64%; p=0.50) were considered (Figure 8E).
E: Secretion of interferon gamma by circulating spike-specific CD4+ T cells; F-H: The proportion of MHD patients with spike-specific CD4+ T cells were compared between the second and third dose of vaccine for optimal- (F), low- (G), and non-responders (H); ns: non-significant.
In contrast with CD4+ T cell response, the third dose of vaccine induced a significant increase in the production of IFN gamma by spike-specific CD8+ T cells of MHD patients: 0 [0 – 0.093] vs. 0 [0 – 0.206] I.U/mL (p=0.015; Figure 9 I). Interestingly, the stronger effect was observed in the subpopulation of MHD patients with no-response after the second dose of vaccine, the proportion with detectable spike-specific CD8+ T cells increases from 17% to 50% between the second and third dose (p=0.09; Figure 9 J-L)
I: Secretion of interferon gamma by circulating spike-specific CD8+ T cells; F-H: The proportion of MHD patients with spike-specific CD8+ T cells were compared between the second and third dose of vaccine for optimal- (F), low- (G), and non-responders (H); ns: non-significant; ****, p<0.0001.
Safety
Local and systemic adverse events and use of anti-pyretic medications within 7 days after the third dose were collected retrospectively, based on a self-assessment questionnaire; tolerability data were available for 63/75 (84%) after the third dose. No patients developed critical side effects requiring hospitalization. Forty-six percent (29/63) reported systemic side effects, including fatigue (32%), chills (16%) and soreness (16%). Forty percent (25/63) developed local side effects, the most frequently reported being pain at the injection site (40%). In almost all cases (74/83, 89%) the intensity of the symptoms was mild or moderate.
2D: second dose; 3D: third dose; pain at the injection site was assessed according to the following scale: mild, does not interfere with activity; moderate, interferes with activity; severe, prevents daily activity; and critical, emergency department visit or hospitalization. Redness and swelling were measured according to the following scale: mild, 2.0 to 5.0 cm in diameter; moderate, >5.0 to 10.0 cm in diameter; severe, >10.0 cm in diameter; and critical, necrosis or exfoliative dermatitis (for redness) and necrosis (for swelling). Fever categories were mild, 38.0°C to 38.4°C; moderate > 38.4°C to 38.9°C; severe, >38.9°C to 40° and critical, >40°C. Medication use was not graded. Additional scales were as follows: fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain (mild: does not interfere with activity; moderate: some interference with activity; or severe: prevents daily activity), vomiting (mild: 1 to 2 times in 24 hours; moderate: >2 times in 24 hours; or severe: requires intravenous hydration), and diarrhea (mild: 2 to 3 loose stools in 24 hours; moderate: 4 to 5 loose stools in 24 hours; or severe: 6 or more loose stools in 24 hours); critical for all events indicated an emergency department visit or hospitalization.
For several side effects, the frequency was higher after the third dose (Figure 11), but the differences were not statistically significant (Note: due to the small sample size?). The authors further note that when the profile of tolerance was compared between MHD patients according to the intensity of the humoral response after the second dose of the vaccine, a significant trend for more side effects was observed in patients with an optimal response (who did not improve significantly their immune response against the spike protein of SARS-Cov-2 after this additional injection; Figure 11).
Optimal (Opt; n=19): same titre than healthy volunteers vs. sub-optimal (S-Opt; n=56): lower titre than healthy volunteers; ****: p<0.0001.
INTERNATIONAL OVERVIEW OF RECOMMENDATIONS ON AN EXTRA/BOOSTER VACCINE DOSE
This section provides an overview of the extra dose (< 6 months following primary vaccination) or the booster dose (> 6 months following primary vaccination) policies across selected countries. Special attention is given to start date of the extra/booster dose campaign, the time between completion of the primer vaccination(b) and administration of the extra/booster dose, target population, vaccine used for the extra/booster dose, and rationale for administering an extra/ booster dose. This section will be updated regularly in function of new information that becomes available.
Table 12 – Overview of extra/booster dose policies across selected countries
| Country | Start date extra/booster dose campaign | Time between primer completion and extra/booster dose | Target population | Vaccine used |
| Canada | Booster vaccination not recommended due to lack of evidence | |||
| Denmark | No indication for a third dose | |||
| France | September 2021 | TBC | Not specified | |
| Germany | September 2021 | 6 months after second dose | Immunocompromised Facilities with vulnerable groups Very elderly living at home | mRNA |
| Israel | August 2021 | Min. 5 months after second dose | People aged over 50 and immunocompromised Priority for people in elderly care facilities and geriatric hospitals | Not specified, likely Pfizer- BioNTech |
| Malta | Mid September 2021 | Immunocompromised and immunosuppressed Residents of elderly care facilities | Not specified | |
| Netherlands | No official decision on booster vaccination | |||
| Sweden | No official decision on booster vaccination | |||
| United Kingdom | September 2021 | Stage 1: Immunosuppressed Residential care homes for elderly Adults aged over 70 16+ considered clinically extremely vulnerable Frontline health and social care workers | Not specified | |
| United States | Regulatory approval as of 12 August 2021 for additional dose mRNA vaccines (Pfizer- BioNTech and Moderna) in certain immunocompromised individuals |
b Second dose for Vaxzevria, Comirnaty, and Spikevax, and first dose for Janssen
Canada
The National Advisory Committee on Immunization does not recommend booster vaccination in its update of 22 July 2021c. It refers to the lack of evidence on the need for booster doses after complete vaccine series and the fact that there is no immunological correlate of protection determined for SARS-COV-2. Therefore, all immunological evidence in support of vaccine efficacy is indirect and cannot directly be used to estimate efficacy.
Denmark
There are currently no signs for introducing a third dose in Denmark.
France
The Conseil d’Orientation de la Stratégie Vaccinale in France has published a recommendation on 6 April 2021d to systematically administer a third dose to the severely immunocompromised, i.e. solid organ transplant recipients, recent bone marrow transplant recipients, dialysis patients, patients with autoimmune diseases on strong immunosuppressive anti-CD20 or anti-metabolite therapy, patients with certain types of lymphoma treated with anti-CD20, and patients with chronic lymphocytic leukaemia. The extra dose is to be administered 4 weeks after the second dose or as soon as possible in case this time period has already passed.
The administered extra dose will be of the same type of vaccine used for the primer vaccination: people that have received an mRNA vaccine will receive a third dose of an mRNA vaccine and people that had received two doses of Vaxzevria will receive a third dose of Vaxzevria. For people aged under 55 who have received a heterologous vaccination regimen (first dose Vaxzevria and second dose an mRNA vaccine) will receive a third dose of an mRNA vaccine.
The extra dose will be administered in the centres where these patients are under treatment, as it was the case for the first and second dose. The estimated magnitude of the target population is 230.000 people.
The rationale for administering an extra dose is the high risk of severe COVID-19 for severely immunocompromised people, the uncertainty around the vaccine effectiveness in this group, and the recent insights that the antibody immune response elicited after two doses of vaccine is insufficient in severely immunocompromised individuals.
The Conseil d’Orientation de la Stratégie Vaccinale recommends that all severely immunocompromised people are prescribed a quantitative anti-S serology test 30 days after the administration of the third dose. It also mentions the need for developing clinical trial protocols evaluating different approaches to increase the immune response of this target population and thus their immunity, in particular to investigate the effectiveness of the recombinant protein vaccines that make use of an adjuvant which may elicit a better response in severely immunocompromised people.
On 5 August 2021, president Macron has announced on social media that France will offer a booster dose to seniors and vulnerable people, citing decline in antibodies and concerns on the Delta variant. The administration will start in September 2021. The precise definition of the target population will be discussed in the week of 9 August 2021(e). The type of vaccine to be used is not yet determined.
People with immunodeficiency or immunosuppression as well as those in need for care and the very elderly living at home should be offered a booster vaccination by their attending physician.
The booster vaccinations will be conducted with one of the two available mRNA vaccines, regardless of the vaccine that was used for the primer vaccination.
The vaccination will be done through the regular health care system channels and with (mobile) teams from the vaccination centres.
In addition, as of September 2021, all German citizens who have been fully vaccinated with a vector vaccine (AstraZeneca or J&J) will be offered further vaccination with an mRNA vaccine, administered via vaccination centres, treating physicians or occupational physicians.
The rationale behind the administration of a third dose are the initial study results that indicate a reduced or rapidly waning immune response after a full COVID-19 vaccination for certain groups, in particular immunocompromised patients, very old people and those in need of care.
Israel
The Israelian Vaccines Operation Committee has on 29 July 2021(g) recommended the administration of a booster dose minimum 5 months after the second dose to all citizens aged over 50(h). People in elderly care facilities and geriatric hospitals should be prioritized.
The Committee refers to the increase in incidence of patients in critical condition among people that are vaccinated, the decrease in neutralizing antibodies, and the decrease in protection against serious illness over time in the context of the Delta variant as justification for the booster. It also mentions that no major safety issues were detected in studies that investigated a third dose and the demonstrated rise in antibody levels following the administration of a booster, and stresses the strong association between the level of neutralizing antibodies and disease protection. Based on this, the committee expects a significant reduction in severe morbidity and mortality in people at risk. The negative impact of isolation, fear, and loneliness on the mental health of the elderly is also taken into consideration.
The administration of a third dose has been subject to debate. On 5 July 2021, the Israelian Ministry of Health wrote in a press releasei that there is neither a recommendation nor a resolution to administer a third dose to the Israeli public and that the third dose does not have any medical protocol or approval from the regulators. At that point in time, an additional dose for people with reduced immune system in whom the regular vaccination protocol yielded low reaction was already promoted. The Committee’s response is that booster administration often occurs prior to FDA approval of a booster protocol. There were other considerations against administration of a booster dose at this point in time. Biopharma companies are developing variant-adapted vaccines. However, these are expected at the earliest in November and considered too late for addressing the experienced need.
The committee countered the need for global equality in terms of covid-19 vaccination by emphasizing the importance of developing evidence on the effectiveness of a booster dose and that Israel is well placed for this given it is the most advanced country with regards to the roll-out of the covid-19 vaccination campaign.
Malta
The Minister of Health announced on 5 August 2021 during a press conference that a booster dose would be rolled out as of mid-September 2021 for people who are immunosuppressed or immunocompromised as a results of a medical condition, and for residents of elderly homes(j). A decision on extending the booster to the wider population has not yet been taken(k).
The Netherlands
The Dutch National Institute for Public Health and the Environment (RIVM) does currently not recommend a third dose for immunocompromised people in an updated advice d.d. 17 June 2021l. It refers to the lack of evidence on the necessity of a booster vaccination for immunocompromised people with the objective to achieve better effectiveness or prolonged duration of protection, as well as the uncertainty around safety and reactogenicity of a third dose. The availability of new data could provoke a change in the recommendation for a booster vaccination for specific patient populations and if vaccines are available.
In another advice, the RIVM states that primer vaccination will be sufficient in almost all cases, apart from severely immunocompromised people. The RIVM is making an inventory of those people for whom a booster vaccination could be beneficial and based on this, the Ministry of Public Health will make a decision on a complementary vaccination for this patient group(m).
Sweden
The Swedish public health authority (Fohm)n is likely to foresee a third dose for a larger proportion of the population in 2022 for which the modalities will depend on, amongst other things, possible new virus variants and the results of various studies on the protective effect of vaccines over time. During the autumn of 2021, certain risk groups, primarily older residents in elderly care homes, people aged over 80 years and people with severely weakened immune systems, may be offered a booster vaccination.
Vaccination against covid-19 will in the next few years in Sweden likely be carried out with mRNA vaccines and possibly an adjuvanted protein-based vaccine.
Sweden foresees four stages in its vaccination against covid-19:
- Stage 1: Mass vaccination of the adult population
- Stage 2: Increase vaccination rate in difficult to reach groups and offer booster to people with the highest risk of serious illness
- Stage 3: Booster for a larger part of the population
- Stage 4: Working on a long-term vaccination programme
United Kingdom
Britain will offer COVID-19 booster vaccines to people aged over 50 or immunocompromised. The roll out is planned to start in September 2021. The estimated number of eligible people is 32 million (approximately half of the population).
The booster will be administered through +2.000 pharmacies across the country with a target of 2.5 million doses administered every week. It is considered to combine the COVID-19 booster vaccination with the regular influenza vaccination.
The decision follows the interim advice of the Joint Committee on Vaccination and Immunisation (JCVI) published on 30 June 2021(o) that indicates to offer a booster programme, if required, in 2 stages from September, starting with those most at risk for serious disease.
Stage 1:
- adults aged 16 years and over who are immunosuppressed
- those living in residential care homes for older adults
- all adults aged 70 years or over
- adults aged 16 years and over who are considered clinically extremely vulnerable
- frontline health and social care workers
Stage 2:
- all adults aged 50 years and over
- all adults aged 16 to 49 years who are in an influenza or COVID-19 at-risk group
- adult household contacts of immunosuppressed individuals
The JCVI did not make a recommendation on the need for a booster vaccination but on the prioritisation of the target population for such a booster, mentioning they would closely follow-up on the emerging scientific data and that the final advice on booster vaccination may change substantially. The UK government did not wait until the final advice of the JCVI to decide upon the design of the booster vaccination campaign(p).
United States
In a joint statement on vaccine boosters of 8 July 2021q, CDC and FDA refer to the fact that people who are fully vaccinated are protected from severe disease and death, including from the variants currently circulating in the country such as Delta. Therefore people who have been fully vaccinated do not need a booster shot at this time. FDA, CDC, and NIH are engaged in a science-based, rigorous process to consider whether or when a booster might be necessary to be prepared for booster doses if and when the science demonstrates that they are needed. On 12 August 2021, the FDA amended the emergency use authorisations of the Pfizer-BioNTech and Moderna COVID-19 vaccines to allow for the use of an additional dose in certain immunocompromised individuals (solid organ transplant recipients or those who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise). The CDC’s Advisory Committee on Immunization Practices will meet on 13 August 2021 to discuss further clinical recommendations. The FDA determined that a third vaccine dose may increase protection in this populationr.
ECDC and EMEA also released a joint statement on 4 August 2021s, referring to the importance of being fully vaccinated for protection against serious COVID-19. As opposed to the joint statement of FDA and CDC, it does not refer to the need for a booster vaccination. The rolling review of heterologous extra/booster vaccination with mRNA vaccines by EMA is ongoing.
ONGOING CLINICAL TRIALS
Belgian planned and ongoing studies using central lab testing
The study endpoints are immunogenicity and reactogenicity. The results of the Sciensano studies are expected November-December 2021 for humoral immune response 4 weeks after third dose and early in 2022 for the cellular immune response.
| Study code and sites | Subjects/Patients | Primo vaccination and third dose | Other parties involved |
| PICOV-VACdose3 Three nursing homes | Staff and residents, no covid-19 history (n=200) | Pfizer +l Pfizer boost at week 36/M9 | Sciensano, Mensura, ULB, ITG |
| Tri-Voice UZA, Maria Middelares | Oncology, ongoing treatment with chemotherapy or rituximab, no covid-19 history (n=200) | Pfizer + Pfizer boost at week 26/M6-M7 | Sciensano, ULB, ITG |
| Nephro3 Hop Erasme | Hemodialysis and renal transplant, no covid-19 history (n=200) | Pfizer +l Pfizer boost at week 26/M6-M7 | Sciensano, ULB, ITG |
| ImRes3 CHU Liège | Allogeneic hematopoietic stem cell transplantation, no covid-19 history (allo- HCT) (n=60) | Pfizer + Pfizer boost at week 26/M6-M7 | Sciensano, ULB, ITG |
| Tri-Voice UZA | Oncology, ongoing treatment with chemotherapy or rituximab, no covid-19 history (n=200) | ChAd-Ox1-S (Oxford- AZ) + Pfizer boost at week 26 /M6-M7 | Sciensano, ULB, ITG |
| Nephro_ID3 UZA | Hemodialysis and renal transplant, no covid-19 history (n=150) | Pfizer + Pfizer boost at week 26 (IM, ID, or 2x ID (both arms)) | Sciensano, ULB, ITG (pending budget approval) |
| Lung3 Hop Erasme | Lung transplant, no covid-19 history (n=65) | Pfizer + Pfizer boost at week 26 | Sciensano, ULB, ITG |
| IMCOVAS KCE trial UA, UGent, ULB, ITG | Healthy volunteers 18- 55y, no covid-19 history (n=560) | Adapted schedules (Pfizer, AZ, Moderna) (no third dose decided yet) | KCE, Sciensano, ITG, ULB, UHasselt |
International studies
| Country & reference | Study | Population | Vaccines | Evaluations | EudraCT/ Clinicaltrials |
| UK60 | Cov-Boost: A randomised, phase II UK multi-centre study to determine reactogenicity and immunogenicity of booster vaccination against ancestral and novel variants of SARS-CoV-2 | Adults 30+ years who are 84 days post second dose | 7 COVID-19 vaccines and half dose of three vaccines and a meningococcal vaccine | Immune responses and safety | Not found |
| Austria | A Randomized, | 150 health | mRNA SARS- | SARS-CoV-2 | 2021-002693- |
| Single-Blind, Phase | subjects, 75 | CoV-2 | antibody | 10 | |
| II Study to Evaluate | >60y (3 | (Biontech/Pfizer | seroconversion | ||
| Safety and Efficacy | arms) | or Moderna) and | rate by week 4 | ||
| to a Third | vector SARS- | after | |||
| Vaccination with a | CoV-2 vaccine | vaccination | |||
| mRNA or Vector | (AstraZeneca) | boost | |||
| Vaccine in Patients | |||||
| under | |||||
| Immunosuppressive | |||||
| Therapy and no | |||||
| Humoral Response | |||||
| after Standard | |||||
| mRNA SARS-CoV-2 | |||||
| Austria | A Randomized, | 60 patients | mRNA SARS- | Difference in | 2021-002348- |
| Parallel Group, | overall | CoV-2 | SARS-CoV-2 | 57 | |
| Single-Blind, Phase | (Biontech/Pfizer | antibody | |||
| 2 Study to Evaluate | or Moderna) and | seroconversion | |||
| the immune | vector SARS- | rate by week 4 | |||
| response of two | CoV-2 vaccine | after | |||
| classes of SARS- | (AstraZeneca) | vaccination | |||
| CoV-2 Vaccines | boost at | ||||
| (COVID-19) | baseline | ||||
| employed as | between 3rd | ||||
| Second Boost in | mRNA SARS- | ||||
| Patients under | CoV-2 | ||||
| current Rituximab | (Biontech/Pfizer | ||||
| Therapy and no | or Moderna) | ||||
| humoral response | and vector | ||||
| after standard | SARS-CoV-2 | ||||
| mRNA vaccination | vaccine | ||||
| (AstraZeneca). | |||||
| US | A Phase II, open- | 549 | Pfizer | Safety and | NCT04949490 |
| label, rollover trial to | participants | Comirnaty™ or | immune | ||
| evaluate the safety | BNT162b2s01 | response | |||
| and immunogenicity | |||||
| of one or two | |||||
| boosting doses of | |||||
| Comirnaty™ or one | |||||
| dose of | |||||
| BNT162b2s01 in | |||||
| BNT162-01 trial | |||||
| subjects, or two | |||||
| boosting doses of | |||||
| Comirnaty™ in |
| Country & reference | Study | Population | Vaccines | Evaluations | EudraCT/ Clinicaltrials |
| BNT162-04 trial subjects | |||||
| Argentina, Brazil, Germany, South Africa, Turkey, United States | A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals | 43 998 healthy volunteers | BNT162b2 at 30 µg and 30 µg BNT162b2SA and third, lower, dose of BNT162b2 at 5 or 10 µg. | Efficacy | NCT04368728 |
| Germany | Immunogenicity of COVID-19 vaccines in medical staff and special risk populations | >1000 healthy volunteers | Pfizer/BioNTech at 30 µg, Janssen (dose not specified), Moderna at 100 µg and Astra-Zene-ca | Immune response | 2021-001512- 28 |
The seven COVID-19 vaccines given as a third dose in the UK trial Cov-Boost are ChadOx1 nCoV-19 (AstraZeneca), BNT162b2 (Pfizer BioNTech), mRNA-1273 (Moderna), NVX-CoV2373 (Novavax), VLA2001 (Valneva), CVnCoV (Curevac), Ad26.COV2.S (Janssen) and the Meningococcal ACWY vaccine. The Novavax, Valneva and Pfizer/BioNTech COVID-19 vaccines as a half dose will be included as well.
reference link: https://kce.fgov.be/sites/default/files/atoms/files/Third%20Covid-19%20vaccination_Report_DUTCH.pdf
