COVID-19 Vaccines & SARS-CoV-2 Variants: Who is winning the Race?

SARS-CoV-2 Vaccines Coming to the Rescue

It was not uncommon to name the year 2020 as annus horribilis as the SARS-CoV-2 quickly spread all over the globe causing the first pandemic in 100 years leading to devastating consequences on health, economy, and the society in general. Neither drugs nor vaccines were available for more or less the whole first year of the pandemic causing devastation, helplessness, and uncertainty. Since the beginning of the COVID-19 pandemic, an estimated 532 million cases and 6.3 million deaths have been recorded worldwide by June 2022. Obviously, the rapid development and emergency use authorization of several COVID-19 vaccines prevented an even more damaging outcome. In this context, both mRNA- (Baden et al., 2021; Polack et al., 2020) and adenovirus-based vaccines (Sadoff et al., 2021; Voysey et al., 2021) have demonstrated vaccine efficacy of more than 90%. Even at the unprecedented mass vaccination scale, the side effects have been mild to moderate although cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) have been detected (Lundstrom et al., 2021). The effectiveness of vaccines and the severity of COVID-19 in vaccinated persons have been compared to non-vaccinated individuals in numerous studies. For example, the efficacy of different types of vaccines, including inactivated virus, mRNA- and adenovirus-based vaccines, in reducing hospitalization rates, disease severity and mortality has been summarized in a meta-analysis based on seven clinical trials involving 1,366,700 participants (Huang and Kuan 2022).There were 4.2 times more cases of COVID-19 in non-vaccinated individuals. Moreover, all types of COVID-19 vaccines which were evaluated, effectively prevented severe disease resulting in improved protection and reduced COVID-19-related deaths. In another study in India, a significant reduction in infection severity, duration of hospital stays, need for ventilation, and death was observed in vaccinated individuals compared to non-vaccinated persons (Balachandran et al., 2022).

SARS-CoV-2: The Mutation Machine?

However, not unexpectedly, mutated forms of the original SARS-CoV-2 Wuhan strain appeared in different parts of the world. These include the BritishB.1.1.7 (alpha) (Leung et al., 2020), the South African B.1.351 (beta) (Mwenda et al., 2021), the Brazilian B.1.1.28.1 (gamma) (da Silva et al., 2021), the Indian B.1.617 (delta) (Das et al., 2021), and the most recent South African B.11.529 (omicron)(Kannan et al., 2021) variant. Due to their potential superiority in transmissibility and pathogenicity compared to the Wuhan strain, they have been named variants of concern. Typically, the novel variants have demonstrated a rapid spread and take-over of previously dominant strains as was originally the case for the D614G mutant (Callaway 2020) and recently the emergence of the omicron variant (Araf et al., 2022). Moreover, offshoots of omicron, named BA.4 and BA.5 have proven slightly more transmissible (Callaway 2022).

A crucial question related to the course of SARS-CoV-2 and the future fate of the COVID-19 pandemic concerns the mutation frequency in SARS-CoV-2 and its comparison to other RNA viruses (Badua et al., 2021). Early sequencing data on SARS-CoV-2 has suggested that sequence changes occur more slowly compared to most other RNA viruses, probably because of the proofreading activity present in the SARS-CoV-2 RNA genome (Callaway 2020). Typically, SARS-CoV-2 has been estimated to accumulate mutations in its genome at half the rate of influenza virus and one-quarter of that of HIV (Callaway 2020). Despite that, mutations have affected infectivity, antigen resistance and other properties as has been demonstrated for mutation hot spots in the spike protein and its receptor binding domain (RBD) (Park et al., 2021). Moreover, certain mutations appear across several different strains and in combination with other mutations may provide complimentary functions. For example, the omicron variant was demonstrated to possess a very high mutation rate at amino acids interacting with angiotensin-converting enzyme 2 (ACE2), the host cell receptor for SARS-CoV-2 (Kim et al., 2021). Furthermore, a systematic comparison of 351,525 full-length viral genome sequences revealed a spectrum of SARS-CoV-2 mutations not seen in other viruses (Yi et al., 2021). An extreme asymmetry with much higher rates of C>U than U>C and G>U than U>G substitutions indicated a directional genome sequence evolution during SARS-CoV-2 transmission, providing insight into the mutational processes in SARS-CoV-2 infections. Moreover, it was demonstrated that there seems to be a trend of increased U-content and reduced SARS-CoV-2 genome size (Wang et al., 2022). It is an open question whether these findings will contribute to faster viral replication, and higher transmissibility but reduced virulence.

How Good is the Protection and How Much Can Boosters Help?

The essential question is obviously how good protection can current vaccines provide against novel SARS-CoV-2 variants? As soon as variants of concern started to emerge, estimations based on modelling, neutralization assays in cell lines and animal studies suggested that the high vaccine efficacy of more than 90% would be reduced. Numerous publications have described the implications of mutations on vaccine efficacy (Ramesh et al., 2021). For example, in a narrative review, the efficacy of COVID-19 vaccines was compared for SARS-CoV-2 variants of concern (Fiolet et al., 2021). The mRNA-based vaccines BNT162b2 and mRNA-1273, the adenovirus-based vaccines ChAdOx1 nCoV-19 and Sputnik V as well as the whole inactivated virus-based CoronaVac vaccine were evaluated for adverse events and efficacy against the alpha, beta, delta and gamma variants. However, as data were collected from PubMed, Google Scholar, BioRxiv, MedRxiv, regulatory drug agencies and pharmaceutical companies until September 2021, data on the omicron variant were not available yet (Fiolet et al., 2021).In the case of alpha, beta, and gamma variants, the mRNA, ChAdOx1 nCoV-19 and CoronaVac vaccines showed effective prevention of symptomatic COVID-19 and severe infections. However, reduced efficacy against the delta variant was observed for the mRNA and ChAdOx1 nCoV-19 vaccines. Moreover, a decline in protection occurred for BNT162b2 and ChAdOx1 nCoV-19 six months after vaccination. Overall, all vaccines were demonstrated to be safe with for example, only rare cases of anaphylaxis (2.5-4.7 cases per 1 million doses) and myocarditis (3.5 cases per 1 million doses) for mRNA-based vaccines. This clearly confirmed that the benefits of COVID-19 vaccination outweighed the risks. In the case of the omicron variant, which possesses a heavily mutated spike protein, reduced neutralization activity in vaccinated individuals has been anticipated (Araf et al., 2022). For example, detectable neutralizing antibodies against the omicron HKU691 and HKU344-R346K strains were detected in only 20% and 24%, respectively, of individuals vaccinated with BNT162b2, whereas no neutralizing antibodies were detected after CoronaVac vaccination (Araf et al., 2022). Moreover, the geometric mean neutralization antibody titers were 35.7-39.9-fold lower for omicron compared to the Wuhan strain in individuals vaccinated with BNT162b2. However, it is anticipated that due to the majority of epitopes targeted by current COVID-19 vaccines, protection in reducing disease severity will be achieved. In another study, the efficacy of the BNT162b2, mRNA-1273 and ChAdOx1 nCoV-19 vaccines has been evaluated for the delta and omicron variants (Andrews et al., 2022).Generally, vaccine effectiveness was higher for the delta variant than omicron related to symptomatic COVID-19. Two doses of ChAdOx1 nCoV-19 were inefficient against omicron. In contrast, two doses of BNT162b2 showed 65.5% efficacy against omicron 2-4 weeks post-vaccination, but the efficacy dropped to 8.8% after 25 weeks.

A common strategy for enhancement of vaccine efficacy has been to in addition to the two mandatory doses of COVID-19 vaccines, although for the adenovirus-based Ad26.COV2.S vaccine a single dose has been sufficient (Sadoff et al., 2021), provide additional third or even fourth booster doses (Editorial, 2021). There has been certain pressure to administer a third vaccine dose, especially to immune compromised individuals and the elderly (Shekhar et al., 2021). Furthermore, in the COV-BOOST phase II trial, seven different COVID-19 vaccines were evaluated for a third booster dose (Munro et al., 2021). Participants were randomly assigned to experimental vaccines and controls in three groups as follows: Group A received initially the NVX-CoV2373 protein subunit vaccine followed by a booster vaccination with half a dose of NVX-CoV2373, ChAdOx1 nCoV-19 or the MenACWY meningococcal vaccine as a control. Group B was given BNT162b2, the inactivated whole SARS-CoV-3 vaccine VLA2001, Ad26.COV2.S or MenACWY. Group C received mRNA-1273, the CVnCOV mRNA vaccine, BNT162b2 or MenACWY. Severe adverse events were uncommon in any vaccination regimen. All booster vaccinations enhanced antibody and neutralizing responses indicating the efficacy of booster doses and also confirming that heterologous immunization with different COVID-19 vaccines was efficacious and safe. Naturally, the emergence of variants of concern has further triggered the necessity to provide booster vaccinations. In this context, third booster vaccinations with BNT162b2 provided high-level protection against the omicron variant indicating a 25-fold increase in neutralizing antibody titers after the booster dose (Araf et al., 2022). Moreover, booster vaccinations with BNT162b2 demonstrated that protection against severe disease can be achieved. In another study, booster immunization with either BNT162b2 or mRNA-1273 after two vaccinations with ChAdOx1 nCoV-19 or BNT162b2 substantially improved protection (Andrews et al., 2022). However, the protection waned over time.

Next Generation Vaccines to End the Pandemic?

Although booster vaccinations have proven useful, the race between the efficacy of current vaccines and emerging novel variants, which continue to appear at a rapid pace, has raised serious concerns. Is the mutation rate too fast for the COVID-19 vaccine development and can re-engineering efforts aid in outpacing novel variants (Kim et al., 2021)? Are the current vaccines efficient enough to turn the pandemic into a seasonal infectious disease as is the case for influenza virus outbreaks or preferentially provide an end toit? Clearly, there is a real potential to re-engineer current vaccines by using molecular modelling and genetic engineering to better target novel SARS-CoV-2 variants by eliciting improved neutralizing antibodies. Obviously, emerging mutations will always be a threat to this strategy. Although the majority of mutations have been identified in the SARS-CoV-2 spike (S) protein, mutations have been also detected in other parts of the genome. One strategy could involve the targeting of other less mutation-prone conservative regions for vaccine development and also to elicit immune responses against a larger number of SARS-CoV-2 specific epitopes and thereby designing a pan-targeting vaccine.
 
A crucial question is whether more efficient vaccines or herd immunity would be able to eradicate SARS-CoV-2? In the case of the SARS epidemic in 2002-2004, the causative agent SARS-CoV suddenly disappeared before any vaccine or drug became available (Bell 2004). Although SARS-CoV and SARS-CoV-2 are related, the main difference seems to be that both asymptomatic and symptomatic COVID-19 occurs, whereas SARS was only detected in a symptomatic form (Hu et al., 2020). For this reason, it was relatively easy to treat all symptomatic SARS patients and prevent the spread of SARS-CoV, which contributed to the eradication of SARS-CoV and led to the end of the epidemic. Unfortunately, we are not in the same position with SARS-CoV-2 and therefore, we need to outsmart the virus, and also stay vigilant and prepared for emerging coronavirus or other viral outbreaks.

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