- - Given the simulation results from modelling studies and reports on the effectiveness of the first dose of COVID-19 vaccine, the delaying-second-dose vaccination strategy might effectively prevent the incidence of SARS-CoV-2 infection.
- - The mix-and-match vaccination strategy, also formally known as the heterologous prime-boost vaccination strategy, is nothing new and has been explored in fighting against other viral infections such as HIV and Ebola.
- - Current evidence suggests that using the heterologous prime-boost vaccination strategy might be safe among vaccine recipients and effective in terms of increasing the levels of neutralizing antibodies against COVID-19. More empirical evidence is urgently needed.
- - Current evidence regarding the heterologous prime-boost vaccination strategy against COVID-19 is very limited in terms of being unable to answer some of the key questions. For instance, how does AstraZeneca-prime/Pfizer-boost compare to Pfizer-prime/Pfizer-boost or AstraZeneca-prime/AstraZeneca-boost in terms of inducing the levels of neutralizing antibodies? Eventually, we also want to know the effectiveness of the heterologous prime-boost vaccination strategy against COVID-19 in the real world. More relevant evidence is urgently needed.
Facing the unprecedented COVID-19 pandemic, decision-makers often act swiftly and make quick decisions to employ public health measures to contain and control the pandemic, even if there is a lack of solid evidence to support the effectiveness and safety of these measures, exemplified by the controversial delaying-the-second-dose and mix-and-match (formally known as heterologous prime-boost) vaccination strategies.
In early 2021, just days after countries like the United Kingdom (UK) announced their policy to delay giving the second dose of COVID-19 vaccine, an OE Original (COVID-19 Vaccines: What Does the Evidence Say about Delaying the Second Dose?) examined available evidence at the time and found very limited empirical evidence which could either support or refute the policy. At the time, we called for urgent generation of relevant empirical evidence but cautious actions before evidence said so.
Despite lack of evidence, a number of countries, such as Canada, Denmark, France, Norway, etc., have adopted the delaying-second-doses strategy, sparking criticism that such countries are endangering their people by carrying out a “population level experiment” (CBC).
Recently, due to concerns over the blood clotting disorder potentially brought by the AstraZeneca COVID-19 vaccine, many countries and regions around the globe, such as Germany, France, and some provinces of Canada, have suspended the use of the AstraZeneca vaccine. This change in vaccination recommendation inevitably causes an issue for those individuals who have received their first dose of the AstraZeneca COVID-19 vaccine and are waiting for their second dose.
A key question we must ask is whether it is safe and effective to receive COVID-19 vaccines other than the AstraZeneca vaccine as the second dose for people who already had AstraZeneca vaccine as the first dose?
In this OE Original, we examine current available evidence with regard to two vaccination strategies against COVID-19, specifically the delaying-second-doses and mix-and-match vaccination strategies, with the aim to identify the evidence-based benefits and risks of these two vaccination strategies.
1. Current evidence on the delaying-second-dose strategy
In this OE Original, we will try to provide some answers to the following two questions with current available evidence: i) How effective is a single dose of COVID-19 vaccine in terms of preventing COVID-19 and related consequences? ii) How effective is the vaccination strategy with a delayed second dose?
1.1 How effective is a single dose of COVID-19 vaccine?
Overall, the majority of empirical evidence indicated that the effectiveness of receiving a single dose vaccine against COVID-19 was acceptable. For instance, a retrospective study posted on MedRxiv suggested an effectiveness of 51% for the Pfizer vaccine in preventing the polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection 13 to 24 days after receiving a single dose of COVID-19 vaccine (Chodick et al., 2021).
The SIREN study (Sarscov2 Immunity and REinfection EvaluatioN), which was a prospective cohort study investigating the effectiveness of the Pfizer vaccine in health care workers in England, found that the effectiveness of a single dose vaccination in the prevention of SARS-CoV-2 infection was approximately 70% (95% CI: 53 to 87%) 21 days after the first dose (Hall et al., 2021).
The Public Health Agency of Canada (PHAC) reported that only approximately 1.3% of individuals got infected with SARS-CoV-2 at least 14 days after receiving their first doses of COVID-19 vaccine (PHAC).
Data from 24 United States (US) hospitals in patients aged 65 and older were recently released by the Centers for Disease Control and Prevention (CDC) (Tenforde et al., 2021). The report showed that the effectiveness of the Pfizer or Moderna COVID-19 vaccines in prevention of hospitalization due to COVID-19 were about 64% [95% confidence interval (CI): 28% to 82%] and 94% (95% CI: 49% to 99%) for partially vaccinated individuals (i.e., single dose) and fully vaccinated people (i.e., two doses), respectively (Tenforde et al., 2021).
Similar to the findings from the CDC, a prospective cohort study published in The Lancet showed that the effectiveness of receiving a single dose of COVID-19 vaccine in reducing hospital admissions due to COVID-19 was about 91% (95% CI: 85% to 94%) and 88% (95% CI: 75% to 94%) 28 to 34 days after vaccination for the Pfizer vaccine and AstraZeneca vaccine, respectively (Vasileiou et al., 2021).
A randomized controlled trial (RCT), recently published in the New England Journal of Medicine (NEJM), investigated the efficacy of a single dose of the Jessen COVID-19 vaccine (Ad26.COV2.S) (Sadoff et al., 2021). Results showed that the vaccine efficacy against moderate, severe, and critical COVID-19 was 66.9% (95% CI: 59% to 73.4%) at least 14 days post vaccination and 66.1% (95% CI: 55% to 74.8%) at least 28 days post vaccination (Sadoff et al., 2021).
Despite the above positive findings, some evidence suggested a very low effectiveness of a single dose of vaccine against COVID-19. For example, an assessment conducted in Qatar showed that the effectiveness of the Pfizer vaccine in preventing PCR-confirmed SARS-CoV-2 infection with the B.1.1.7 variant and with the B.1.351 variant were only 29.5% (95% CI: 22.9% to 35.5%) and 16.9 (95% CI: 10.4% to 23%), respectively (Abu-Raddad et al., 2021). Moreover, the vaccine effectiveness of either variant against severe, critical, and fatal COVID-19 was only around 39.4% (95% CI: 24% to 51.8%) (Abu-Raddad et al., 2021).
1.2 How effective is the vaccination strategy with a delayed second dose?
A model-based study showed that a single-dose vaccine against COVID-19, which has an efficacy of 55% and takes 2 weeks to achieve lifetime protection, could prevent as many SARS-CoV-2 infections as a 2-dose vaccination strategy, which has an efficacy of 95% and requires 4 weeks to achieve full efficacy, could (Paltiel et al., 2021). If the duration of protection was 6 months, the efficacy required for a single-dose COVID-19 vaccine was about 75% in order to prevent as many infections as a 2-dose COVID-19 vaccine with an efficacy of 95% could (Paltiel et al., 2021).
A preprint, using a mathematical model, illustrated that if the efficacy of a single-dose was high (72% in the model), the single-dose vaccination would be the optimal strategy which can prevent up to 22% additional deaths among older patients than the two-dose strategy (Matrajt et al., 2021). If the efficacy of a single-dose vaccine was low to moderate (18% to 45% in the model), then vaccinating all older adults with mixed strategies would be the best option (Matrajt et al., 2021).
A modeling study conducted by Moghadas et al. (2021) revealed that the vaccination strategy with delaying the second dose of the Moderna vaccine by at least 9 weeks could actually maximize the effectiveness of vaccination against COVID-19 by preventing17.3 additional infections per 10,000 persons [95% credible interval (CrI): 7.8 to 2.9], 0.69 hospitalizations per 10,000 persons (95% CrI: 0.52 to 0.97), and 0.34 deaths per 10,000 persons (95% CrI: 0.25 to 0.44), compared to the recommended 4-week interval. Compared to the recommended interval between 2 doses of the Pfizer vaccine, adoption of the vaccination strategy with delaying the second dose of the Pfizer vaccine by 9 weeks could prevent additional 0.60 hospitalizations per 10,000 persons (95% CrI: 0.37 to 0.89) and 0.32 deaths per 10,000 persons (95% CrI: 0.23–0.45) but failed to show advantages in preventing SARS-CoV-2 infection unless the efficacy of the first dose of the Pfizer vaccine did not wane over time (Moghadas et al., 2021).
With a simulation agent-based model, Romero-Brufau et al. (2021) demonstrated that delaying the second dose would be an optimal strategy when efficacies of a single-dose COVID-19 vaccine were at least 80% (i.e., The median cumulative mortality per 100,000 people for delayed second dose vs. two-dose was 179 vs. 226 with a first dose vaccine efficacy of 90% and 207 vs. 233 with a first dose efficacy of 80%).
Currently, there is little evidence shedding light on the effectiveness of the delaying-second-dose COVID-19 vaccine strategy. An empirical study, posted on MedRxiv on May 17th, 2021, found that the peak antibody response was 3.5-fold higher in older adults who had received Pfizer COVID-19 vaccine with a delayed second dose (i.e., 12 weeks between first and second doses), compared to those who had two doses of vaccine with a standard interval (Parry et al., 2021). This study suggests a better antibody response in those receiving a delayed second dose. However, cellular response, which might play an important role in supporting and maintaining antibody production, was much lower (3.6-folder lower) in the delaying-second-dose group, leaving us further questions and uncertainty (Parry et al., 2021).
2. Mix-and-match vaccination strategy (heterologous prime-boost vaccination strategy)
As we mentioned previously, individuals who have received the AstraZeneca vaccine for their first dose must face the reality that they might have to receive a different COVID-19 vaccine for their second dose because the AstraZeneca vaccine has been suspended by many countries due to safety concerns.
In this OE Original, it is not within our scope to discuss whether the decision of suspension was really evidence-based or not. Yet it is urgent for us to examine current available evidence with regard to the efficacy and safety of the mix-and-match vaccination strategy.
The mix-and-match vaccination, which is called heterologous prime-boost vaccination, involves different formulations used in the prime and boost regimens. Research on the mix-and-match vaccination strategy against viral infections started in the 1990s with the aim to develop vaccines against human immunodeficiency virus (HIV) (Hu et al., 1991; Hu et al., 1992). The mix-and-match vaccination has been found to be a promising way of fighting against HIV in clinical trials (Gray et al., 2019; Karasavvas et al., 2012).
There are different methods of the heterologous prime-boost vaccination strategy on the basis of different vaccine platforms (e.g., DNA vaccine, viral vector-based vaccine, etc.). Targeting viruses like HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), ebolavirus, and avian influenza virus, researchers have so far explored various combinations for heterologous the prime-boost vaccination strategy, such as DNA vaccine-prime/viral vector-based vaccine boost or vice versa and protein-based vaccine prime/viral vector-based vaccine boost or vice versa (Kardani et al., 2016).
In terms of mix-and-match strategy in vaccination against COVID-19, empirical evidence is very limited. A Chinese study, using a mouse model, investigated the outcomes of adopting the heterologous prime-boost strategy with four types of leading COVID-19 vaccine candidates undergoing clinical trials in China (He et al., 2021). Results showed that adenovirus-vectored vaccine-prime/inactivated or recombinant subunit or mRNA vaccine-boost resulted in an increased level of neutralizing antibodies and promotion of the modulation of antibody responses to predominantly neutralizing antibodies in mice (He et al., 2021).
A UK trial, which investigated the heterologous prime-boost vaccination strategy (different combinations of the AstraZeneca and Pfizer vaccines) against COVID-19, reported initial reactogenicity data (Shaw et al., 2021). The heterologous prime-boost strategy induced greater systemic reactogenicity with an increased paracetamol usage, compared to the homologous strategy. Immunogenicity results will be available soon.
A Russian clinical trial assessed the outcomes of heterologous prime-boost strategy with two different types of replication-deficient adenovirus vector-based vaccines (i.e., type 26-prime/type 5-boost) (Logunov et al., 2021). Replication-deficient adenovirus type 26-prime/type 5-boost was well tolerated among participants and showed a vaccine efficacy of about 91.6% (95% CI: 85.6% to 95.2%) (Logunov et al., 2021).
The CombivacS trial is a phase II RCT conducted in Spain aiming to determine the safety and immunogenicity of a dose of the Pfizer vaccine in individuals who have previously received a dose of the AstraZeneca vaccine (i.e., AstraZeneca-prime/Pfizer-boost). The hypothesis was that the immunogenicity would be greater in the group that receives AstraZeneca-prime/Pfizer-boost, compared to those who received a single dose of AstraZeneca vaccine only. Initial results from the CombivacS trial revealed a potent immune response induced by the AstraZeneca vaccine-prime/Pfizer vaccine-boost strategy: There was a 150-fold increase in antibody titers 14 days after the heterologous boost dose was administered. The AstraZeneca vaccine-prime/Pfizer vaccine-boost strategy was also safe with no adverse events requiring extra medical attention or hospitalization. Only local side effects occurred in a total of 663 participants, such as headache (44%), malaise (41%), and chills (25%).
Evidence with regard to the effectiveness of delaying the second dose of COVID-19 vaccine is quickly accumulating. Based on simulation results from modelling studies and reports on the effectiveness of the first dose of COVID-19 vaccine, it seems that the delaying-second-dose vaccination strategy might effectively prevent the disease and contain the pandemic.
There is very limited evidence regarding the efficacy and safety of the heterologous prime-boost vaccination strategy (or mix-and-match strategy) in combating with COVID-19, although the heterologous prime-boost vaccination strategy is nothing new and has been explored in fighting against other viral infections such as HIV and Ebola.
Current evidence suggests that this vaccination strategy might be safe and effective in terms of increasing the levels of neutralizing antibodies in vaccine recipients. Current evidence, although helpful, is very limited in terms of being unable to answer some of the key questions. For instance, how does AstraZeneca-prime/Pfizer-boost compare to Pfizer-prime/Pfizer-boost or AstraZeneca-prime/AstraZeneca-boost in terms of inducing the levels of neutralizing antibodies? Eventually, we also want to know the effectiveness of the heterologous prime-boost vaccination strategy against COVID-19 in the real world. Thus, more relevant evidence is urgently needed.
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