Malays J Pathol 2021; 43(2): 203 – 217

REVIEW ARTICLE COVID-19 vaccines and herd immunity: Perspectives, challenges and prospects

Rebecca S.Y. WONG*

Faculty of Medicine, SEGi University. No. 9, Jalan Teknologi, Taman Sains Selangor, Kota Damansara, PJU 5, 47810 Petaling Jaya, Selangor, Malaysia.

Abstract

The coronavirus disease 2019 (COVID-19) is one of the biggest public health threats in the 21st century. Nearly every country in the world has been affected by COVID-19. The magnitude of the problem, with over 179 million confirmed cases and 3.8 million deaths worldwide, has driven researchers to search for vaccines to combat the disease. The discovery and development of a new vaccine, from the initial stage to the vaccine finally reaching the patients, usually take many years. However, given the urgency of the situation, many clinical trials on the COVID-19 vaccines have been conducted at extraordinary speed, whereas several vaccines against SARS-CoV-2 are being administered worldwide. This article gives an overview of the different types of COVID-19 vaccines, with a focus on those with promising results and are commonly used worldwide. It also gives an overview of herd immunity and discusses the challenges in achieving herd immunity through the global vaccination campaigns. Last but not least, some strategies that may be used to address these challenges are discussed.

Keywords: COVID-19, SARS-CoV-2, pandemic, vaccine, herd immunity

INTRODUCTION started a race against time to explore the use of various drugs to combat the disease. However, The coronavirus disease 2019 (COVID-19) to this end, there is no definitive or curative is caused by an infectious agent known as drug for COVID-19. The current treatment severe acute respiratory syndrome coronavirus of COVID-19 is mainly symptomatic. On the 2 (SARS-CoV-2, previously known as 2019- other hand, many pharmaceutical companies are nCoV). The disease has spread uncontrollably working round the clock to develop vaccines across the world since its emergence in December against SARS-CoV-2 in an attempt to break the 2019. As of 21st June 2021, there were more than chain of transmission. Some companies such as 179 million confirmed cases of COVID-19 with Pfizer,2 Moderna3 and AstraZeneca4 have reported more than 3.8 million people losing their lives to that their vaccines are highly effective against the disease.1 With a high number of confirmed SARS-CoV-2 infection which brings great hope cases and deaths every day, the world is now to the world that the pandemic may be under facing one of the most challenging health threats control in the near future. of the 21st century. The disease has caught the At present, several vaccines are being attention of scientists, healthcare professionals investigated or have obtained authorisation and government authorities globally. Identifying for emergency use across the globe. These and treating infected individuals, as well as vaccines have been developed based on different preventing the spread of COVID-19 have become technologies and their efficacies vary, but they the top priorities worldwide. all serve a common purpose, i.e. to induce active Ever since the emergence of COVID-19 acquired immunity against SARS-CoV-2 with in December 2019 and the declaration of the aim to reduce the spread of COVID-19 or COVID-19 as a pandemic by WHO in March the severity of disease, in case a vaccinated 2020, many pharmaceutical companies have

*Address for correspondence: Rebecca S.Y. Wong, Faculty of Medicine, SEGi University. No. 9, Jalan Teknologi, Taman Sains Selangor, Kota Damansara, PJU 5, 47810 Petaling Jaya, Selangor, Malaysia. Phone: +603-6145 1777 (ext. 3616). Fax: +603-6145 2649. Email: [email protected]. my; [email protected]

203 Malays J Pathol August 2021 person is infected. The fi rst part of the article be feasible for vaccine development to follow gives an overview of the different types of the usual time frame due to the urgency of the vaccines used in COVID-19 with regards to situation. To speed up the process, various phases the current state of science related to vaccine are carried out in parallel but the usual safety technologies and effi cacies. The second part of and effi cacy monitoring mechanisms are strictly the review discusses herd immunity, as well as followed.6 It is noteworthy that not all drugs and the challenges faced in achieving herd immunity vaccines will end up in the market after many against SARs-CoV-2 infection through the global years of hard work and millions of research vaccination campaigns. funds being exhausted. In general, the success rate depends on the type of research. Wong et 1. Vaccine development for COVID-19 al. estimated the probability of success for drug Even though pharmacotherapy may alleviate and vaccine clinical trials and reported an overall symptoms in some cases of COVID-19, one success rate of 13.8%. However, the probability of success for infectious disease vaccine alone important way to bring the pandemic to a halt, 7 so that the world will be back to normalcy, is was estimated to be 33.4%. to come up with vaccines that can slow disease 1.2. Types of vaccine against SARS-CoV-2 spread or even break the chain of transmission. Therefore, vaccine development plays a vital Currently, there are six main types of vaccines role in COVID-19 research. that have reached various stages of vaccine development i.e. 1) nucleic acid (DNA or RNA) 1.1. Stages of vaccine development vaccines, 2) protein-based vaccines, 3) live Under normal circumstances, the development attenuated virus vaccines, 4) inactivated virus of a vaccine usually takes many years. It can vaccines 5) virus-like particle vaccines and 6) be divided into four main stages: 1) exploratory virus vector vaccines. For nucleic acid vaccines, stage, 2) preclinical stage, 3) clinical stage either DNA or RNA is inserted into the human and 4) post-marketing stage. Each stage has host cells to produce the viral protein required many stringent requirements by the regulatory to stimulate an immune response in the host. authorities such as the FDA. Using the FDA For live attenuated virus vaccines, the weakened guidelines as an example, the usual stages of but non-infectious live virus is injected, which 5 stimulates an immune response similar to that vaccine development are summarised in Fig. 1. of a natural infection. For inactivated virus However, in the case of COVID-19, it will not

FIG. 1: Stages of vaccine development

204 COVID-19 VACCINE AND IMMUNITY vaccines, the dead and harmless virus is injected 2.1. Pfizer/ BioNTech vaccine while protein subunit vaccines usually contain The Pfizer/BioNTech vaccine (BNT162b2) is a synthetic antigenic component of the virus an mRNA vaccine. The results of the Phase (e.g. spike protein). Virus-like particle vaccines III clinical trial were reported in a recent consist of empty, non-infectious virus shells and publication by Polack et al. The multinational viral vector vaccines are made up of genetically study involved 43,548 participants aged > 16 engineered viral vectors (e.g. adenovirus) to years, who were randomly assigned to receive produce coronavirus proteins in the body.6, 8-11 All either placebo (n=21,728) or the RNA vaccine of them have their advantages and disadvantages candidate (n=27,720). Two doses of the injection and are summarised in Figure 2. were given 21 days apart. Subsequently, 18,556 received the second dose of BNT162b2 (with 48 2. Candidate vaccines with reported vaccine discontinued the trial), and 18,530 received the efficacy second dose of placebo (with 95 discontinued Several pharmaceutical companies have reported the trial). Among those who completed the the efficacy of their vaccines either in the second dose, there were 8 cases with confirmed published literature or in their press release. COVID-19 in the vaccinated group, versus 162 Some of these vaccines have already been cases in the placebo group, giving an efficacy of approved for early, emergency or conditional 95% (95% confidence interval [CI], 90.3 to 97.6). use in many countries. This section gives an The study also reported >99.99% probability of update on vaccines with reported efficacy and/ a true vaccine efficacy, which greatly exceeded or approved use for various purposes. the minimum criteria for EUA (i.e. >98.6%

FIG. 2: Types of COVID-19 vaccines, how they work and their advantages and disadvantages.

205 Malays J Pathol August 2021 probability of true vaccine efficacy being greater recombinant adenovirus (rAd)-based) produced than 30%). The efficacy was consistent across by the Gamelaya Research Institute of age, gender and race and the vaccine was well- Epidemiology and Microbiology in Russia. tolerated with four participants reported serious Logunov et al. reported the preliminary findings adverse effects (injection-related shoulder injury, from interim analysis of their Phase 3 clinical axillary lymphadenopathy, leg paresthesia and trial. Two doses of the vaccine were administered paroxysmal ventricular arrhythmia). Two deaths in a 21-day interval by intramuscular injection. were reported from the vaccinated group and four Both doses (rAd26 and rAd5) were viral from the placebo group, but were considered vectors that carried a full-length gene encoding unrelated to the vaccine or placebo.12 a glycoprotein S of SARS-CoV-2. Of the total 21,977 adult participants, 16,501 were assigned 2.2 Moderna vaccine to the vaccine group and 5,476, control group, The Moderna vaccine is an mRNA vaccine. and 19,866 were given two doses of either Following Pfizer’s announcement, Moderna the vaccine or placebo. The study reported 16 reported key findings of its primary efficacy (0.1%) and 62 (1.3%) confirmed COVID-19 analysis of the Phase III COVE study on 30th cases in the vaccine group and control group November 2020 in a press release.3 Results of the respectively, giving a vaccine efficacy of 91.6% study were later published in the New England (95% CI 85·6–95·2). Four deaths were reported Journal of Medicine by Baden et al. in February but were considered unrelated to the vaccine 2021. A total of 30,420 volunteers were enrolled and the vaccine was generally well-tolerated.15 in the trial. They were randomly assigned either vaccine or placebo in a 1:1 ratio (n=15,210 2.5 Johnson and Johnson vaccine in each group). The participants received two The Johnson and Johnson vaccine is an injections of vaccine (100 µg) or placebo adenovirus-based given in intramuscularly, 28 days apart. There were a single dose. Recently, Johnson and Johnson 185 confirmed COVID-19 cases in the placebo released the findings of its Phase III ENSEMBLE group, versus 11 in the vaccinated group. The study. It was reported that after 28 days of study concluded that the mRNA-1273 vaccine vaccination, its Janssen COVID-19 vaccine candidate demonstrated a 94.1% efficacy against candidate, Ad26.COV2.S, had a 66% overall COVID-19 and was well-tolerated in general efficacy in preventing moderate (defined as without any serious adverse effects. The efficacy presence of pneumonia, abnormal O2 saturation/ was consistent across age, gender and race.13 shortness of breath, abnormal respiratory rate, presence of deep vein thrombosis or >2 systemic 2.3 AstraZeneca vaccine symptoms) to severe (defined as signs of severe The AstraZeneca vaccine is a viral vector systemic illness, intensive care unit admission, vaccine. The interim primary efficacy analysis of respiratory or organ failure, shock, death etc.) AstraZeneca’s four randomised controlled trials COVID-19 and the efficacy in the US, Latin (COV001, COV002, COV003 and COV005, America and South Africa were 72%, 66% and n=11,636) on the vaccine candidate AZD1222 57% respectively, with a complete protection reported a vaccine efficacy of 62.1% (when given against hospitalisation and death related to as a one-dose regime of two standard doses; COVID-19. When it comes to prevention of n=2,741) and 90% (when given as a two-dose severe COVID-19 alone, the vaccine candidate regime of a low dose followed by a standard demonstrated an 85% efficacy across all studied dose one month apart; n=8,895). This gives an regions in those >18 years of age. Interestingly, overall efficacy of 70%. ADZ1222 was well- nearly 95% of the confirmed cases in South tolerated for both regimes. There were 175 severe Africa in this study involved a SARS-CoV-2 adverse events in 168 participants, of which 84 variant from the B.1.351 lineage.16 occurred in the vaccinated group and 91 in the control group. Out of these 175 adverse events, 2.6 Novavax vaccine 3 were considered as possibly related (2 in the The Novavax vaccine candidate, NVX- control group and 1 in the vaccinated group).3,14 CoV2373, is a protein . A genetic sequence of a spike protein of SARS- 2.4. Sputnik V vaccine COV-2 encodes for the purified protein used Gam-COVID-Vac (also known as Sputnik V in NVX-CoV2373, which is produced using vaccine) is a viral vector vaccine (heterologous recombinant nanoparticle technology. On 28th

206 COVID-19 VACCINE AND IMMUNITY

Jan 2021, Novavax reported an overall vaccine 100% for severe cases. However, the data has efficacy of 89.3% (95% CI: 75.2 – 95.4) via its not been released officially by the Pakistan press release based on 62 confirmed COVID-19 government or CanSino.18 cases (n=56 for placebo group; n=6 for vaccine group) for their Phase III UK clinical trial, which 2.8 Other vaccines enrolled >15,000 participants aged between 18 Vaccines by Sinovac and Sinopharm are and 84 years, with 27% > 65 years. Among these inactivated virus vaccines. China has approved cases, there were 61 mild to moderate cases the use of these two vaccines in the general public (overall) and 1 severe case (placebo group). It is on 31st Dec 2020 and 7th Feb 2021 respectively.19 noteworthy that when the efficacy was analyzed No official data on the efficacy of Sinopharm based on SARS-CoV-2 strains, a 95.6% efficacy vaccine has been released but China National was reported for the original strain and an 85.6% Biotec Group (a subsidiary of Sinopharm) was reported for the UK variant strain.17 claimed that the vaccine has an efficacy of 79.34%.20 For Sinovac, the efficacy ranged from 2.7 CanSino Vaccine 50.65% to 83.5%, according to trial data from AD5-nCOV (trade name Convidicea) is a single- China, Brazil, Indonesia and Turkey.20,21 Various dose candidate viral vector vaccine developed types of vaccines used against SARS-CoV-2 by China’s CanSino Biologics Inc. Unofficially, infection are summarised in Table 1. Pakistan reported that the vaccine has an overall efficacy of 65.7% in preventing symptomatic 3. Overview on herd immunity COVID-19 and 90.1% in preventing severe Acquired immunity to a disease can be either COVID-19. AD5-nCOV demonstrated a higher active or passive. Passive immunity is something efficacy for a subset of 30,000 participants in a person acquires from someone else (e.g. Pakistan i.e. 74.8% for symptomatic cases and antibodies from mother to baby) or something

TABLE 1: Summary of COVID-19 vaccines with promising results

Company/ Vaccine type Vaccine Dosage/ Efficacy Reference Institution Candidate Storage Pfizer/ mRNA Comirnaty/ 2 doses/ 95% [12] BioNTech BNT162b2 -70℃

Moderna/ mRNA mRNA-1237 2 doses/ 94.1% [13] NIAID 2 to 8℃ AstraZeneca/ Viral vector ADZ1222 2 doses/ 70% [14] Oxford University 2 to 8℃ Gamelaya Viral vector Sputnik V 2 doses/ 91.6% [15] Research Institute 2 to 8℃

Janssen Vaccines Viral vector Ad26.COV2. S Single 66% [16] (Johnson & dose/ Johnson) 2 to 8℃ Novavax Inc Protein subunit NVX- 2 doses/ 89.3% [17] CoV2373 2 to 8℃ CanSino Viral vector AD5-nCOV/ Single 66% [18] Biologics Inc Convidicea dose/ 2 to 8℃ Sinopharm Inactivated BBIBP-CorV 2 doses/ 50.65-83.5% [20] virus 2 to 8℃ Sinovac Inactivated CoronaVac 2 doses/ 79.34% [20, 21] virus 2 to 8℃

207 Malays J Pathol August 2021 else (e.g. antibodies from convalescent plasma). to determine the herd immunity threshold for On the other hand, a person develops active SARS-CoV-2 simply because many factors need immunity either by exposure to the infection to be taken into consideration when calculating or via vaccination (Figure 3A). Herd immunity the herd immunity threshold. One of the factors is a type of active acquired immunity. One affecting the herd immunity threshold is the dictionary defines herd immunity as “protection reproductive number (R0) which refers to the within a population against a particular disease number of uninfected people that can be infected where a great majority of people are immune to by an infected person in a naïve population. The the disease, especially because they have been R0 varies from country to country and differences vaccinated against it” (Figure 3B).22 The key here exist even in different parts of the same country.26 is “a great majority of people are immune” and For SARS-CoV-2 infection the R0 can range to achieve this, vaccination is the way forward from 1.64 to 6.49.27 as having a great majority of people infected to Mathematically, it is possible to calculate the achieve herd immunity will mean a high number herd immunity threshold by using the formula of deaths. 1-1/ R0. However, the number of susceptible people for any given population changes as 3.1 Herd immunity threshold the pandemic evolves. Therefore, the effective

More than a century ago, Kermack and reproductive number (Rt) is sometimes used Mckendrick carried out a mathematical instead. Kwok et al. conducted a study to investigation on the progress of an epidemic. determine the herd immunity threshold using

It was concluded that a threshold exists in a 1-1/Rt in 32 countries and reported that a wide homogenous population and is dependent on range from 5.66% to 85% existed. This is not factors that are specific to the epidemic such as surprising because Rt differs greatly in different recovery rate, death rate and infectivity. If the countries, which may be influenced by various proportion of susceptible individuals is below this preventive measures implemented by each threshold, then no epidemic is likely to occur. country.28 However, these calculations say very However, a small increase in the infectivity rate little about human behaviour and the changes may result in large epidemics. In general, an that take place within the population. Even if epidemic can come to an end even before the a country does reach the calculated threshold, exhaustion of all the susceptible individuals in pockets of outbreak may still occur in areas the population.23 where the vaccination rates are low. Today, we know that to achieve herd immunity, Another factor that makes it difficult to a certain percentage of the population needs to determine the herd immunity threshold in be immune to the disease. Once this level of SARs-CoV-2 infection is that the duration of herd immunity is reached, people who are not the immunity after COVID-19 is unclear and immunised will be protected by those who are and contradicting findings exist in the published this is referred to as the herd immunity threshold. literature. Unlike the lifelong immunity that The herd immunity threshold is different from develops after measles or rubella infections, disease to disease as many factors contribute serial measurements of IgG antibodies against to the herd immunity threshold. Typically, the SARS-COV-2 in patients with mild COVID-19 herd immunity threshold for contagious diseases revealed a rapid decay of antibodies within 3 ranges from 70-90%. For example, for measles, months post-infection.29 Research has also shown this threshold is about 90-95%, for polio, about that a greater reduction in IgG levels occurred 60-97% and for smallpox, about 80%. Thus far, in patients who were symptomatic compared smallpox is the only disease in the history of to those who were asymptomatic. In the early mankind that has been successfully eradicated convalescent phase, 40% of asymptomatic since 1979 as a result of vaccination.24 and 12.9% of symptomatic individuals were observed to be seronegative.30 Another study, on 3.2 Herd immunity threshold for SARS-CoV-2 the other hand, showed that antibodies against infection SARS-CoV-2 lasted more than 8 months after Even though some have estimated that the herd mild infection in which high seropositivity rates immunity threshold for COVID-19 ranges from ranging from 69.0% to 91.4% were reported.31 60% to 70%,25 the proportion of the population Reinfection after recovery further complicates that needs to be vaccinated to achieve herd estimation of herd immunity threshold for SARS- immunity remains largely unknown. It is difficult CoV-2 infection. Tillett et al. reported the first

208 COVID-19 VACCINE AND IMMUNITY

FIG. 3. (A) Acquired immunity and (B) how vaccination protects susceptible individuals in the population from being infected through herd immunity. case of reinfection of SARS-CoV-2 in the United to be under reported due to diffi culties in getting States backed by genomic evidence. Reinfection the samples from the two separate infections has also been reported in other countries.32 In for comparison of viral genomic differences. some cases, the reinfection was more severe than Reinfection tells us that depending on natural the fi rst infection, in others, it was milder.33-35 infection to achieve herd immunity may not be The number of re-infected cases is very likely a practical approach.

209 Malays J Pathol August 2021

4. COVID-19 vaccines and herd immunity doses being administered worldwide each day. Many people have questioned the possibility The top countries with a high percentage of of achieving herd immunity for COVID-19 the population fully vaccinated are Seychelles through vaccination. Even though many countries (69.3%), Bahrain (60.0%), Israel (56.9%), Malta have started their vaccination programs, the (57.9%) and Mongolia (49.7%).19 However, uncertainties in achieving herd immunity remain despite the exponential rate in vaccinating people as there are numerous challenges ahead. This globally, many countries have vaccinated less section discusses some of the challenges faced than 1% of their population,19 which shows a in achieving herd immunity for COVID-19 great disparity in the distribution and availability (Figure 4). of vaccines in different countries. In the Economic and Social Council’s Special 4.1 Unequal distribution of vaccines Ministerial Meeting, vaccine inequity was Low- and middle-income countries (LMICs) viewed as a challenge during this unprecedented are often slow in medical and technological pandemic and the Director-General of WHO advances. In comparison to the high-income reported that 82% of the administered vaccine countries (HICs) or upper-middle-income doses at the point of the meeting took place in countries (UMICs), the LMICs may be at a HICs or UMICs, whereas the LICs only received disadvantage in getting adequate supplies of about 0.2% of the total administered doses. HICs the COVID-19 vaccines. The LMICs need help have 1 in 4 people vaccinated but in poorer if the world were to reach herd immunity and countries the ratio was about 1 in 500. The return to normalcy. Director General of the World Trade Organization As of 21st June 2021, more than 2.62 billion (WTO), on the other hand, considered such shots of vaccine against SARS-CoV-2 have been disparities and inequity in vaccine distribution given in 180 countries, with about 19.2 million as “morally unconscionable”.36

FIG. 4: Challenges faced in achieving herd immunity for COVID-19

210 COVID-19 VACCINE AND IMMUNITY

4.2 Different efficacies for different vaccines reluctant to get vaccinated. A systematic review Differences in vaccine efficacy discussed and meta-analysis of 28 studies revealed a decline in Section 4 may pose a challenge to the in vaccine intention and an increase in vaccine achievement of herd immunity. While some refusal. When studies were conducted earlier vaccines demonstrated >90% of efficacy, others (March to May 2020; n=18), the proportion of only showed an efficacy of approximately 50%. those who intended to vaccinate versus those With these differences, it is even harder to who did not intend to vaccinate was 79% versus determine the percentage of the population to be 12%. Later studies conducted from June to immunised to reach herd immunity threshold as October 2020 (n=10) reported the proportion to several vaccines may be used within the same be 60% versus 20%. Some of the factors that population due to supply shortages. To overcome were associated with vaccine refusal include this problem, some researchers have suggested being female, being younger, having a lower mixing two or more COVID-19 vaccines and education or income level or belonging to an believed that this could expedite the global ethnic minority in the population.42 vaccination campaign and enhance the immune One study investigated three factors that response.37 This approach of vaccination is influence vaccine acceptance in the United known as heterologous prime-boost, which can States, i.e. efficacy of vaccine, minor side effects be dated back to 1992 in the early efforts of HIV and severe adverse effects. Vaccine efficacy vaccine development.38 was demonstrated to have the greatest effect In one study, different types of vaccines in influencing vaccine acceptance, followed by (adenovirus vector, inactivated/recombinant severe adverse effects and minor side effects.43 subunit and mRNA vaccines) were administered In a study involving 1144 participants, as high into mice either alone or in a heterologous as 36.8% of the respondents answered “no” prime-boost manner. It was reported that the when asked about their intent to be vaccinated, heterologous prime-boost approach yielded whereas 26.4% answered “not sure”. Some of the higher levels of neutralising antibodies and reasons include concerns over efficacy, safety, modulated the antibody responses. Responses side effects as well as the rigor of testing, which of Th1-biased T cells were also observed to be resulted in a lack of trust in the vaccines.44 enhanced.39 In a preprint, another study reported In April 2021, the European Union and some that the administration of one dose of ChAdOx1 other countries announced to suspend or stop nCOV-19 (AstraZeneca) prime followed by a using AstraZeneca vaccine45 due to reported BNT162b2 (Pfizer/BionTech) boost 8 weeks cases of blood clots in those who received the later resulted in potent immune responses. vaccine even though it was claimed that the Individuals who received the heterologous prime- incidence of blood clots is “extremely rare” boost regimen demonstrated potent neutralising previously. In an article published by the British activity against the Alpha variant (B.1.1.7), Beta Medical Journal, 79 people have been reported variant (B.1.351) and Delta variant (B.1.617). with blood clots and low platelets (of which 19 Interestingly, the heterologous prime-boost had died), among >20 million people who have yielded a 3.9-fold higher neutralising activity been given AstraZeneca vaccine in the United when compared to the homologous BNT162b2 Kingdom. This is equivalent to a probability of 1 regime against the Alpha variant. In the same out of 250,000. Most of the cases of thrombosis study, potent T cells reactivity (both CD4+ occurred in women who were under 60 years.46 and CD8+) was also observed, whereas the Despite the claims that there was no causal heterologous prime-boost approach was not relationship between the vaccine and thrombosis associated with serious adverse effect.40 and that the chance of having thrombosis is small, these reported cases have led to setbacks of the 4.3 Vaccine hesitancy AstraZeneca vaccine in European and other In 2019, WHO identified vaccine hesitancy countries, with some countries restricting the use as one of the top ten health threats facing the of the vaccine in people aged 60 or below.47 Such world. Vaccine hesitancy refers to the refusal news in the main stream media might influence or reluctance in getting vaccinated even when the confidence of the public regarding the safety a vaccine is available.41 As long as a large of COVID-19 vaccines. proportion of the population refuse to get vaccinated, herd immunity remains a distant 4.4 Duration of vaccine-induced immunity dream. There are many reasons why people are The duration of vaccine-induced immunity

211 Malays J Pathol August 2021 remains largely unknown at this point. This is first detected in Japan/Brazil), B.1.351 (Beta, something that only time can tell as the vaccine first detected in South Africa), B1.617.2 (Delta, campaigns in many countries have started less first detected in India), B.1.427 and B.1.429 than a year ago. Given the different efficacies (Epsilon, both first detected in the US) belong of the various vaccines and varying immune to VOC. These variant strains have demonstrated responses by different individuals, more studies increased transmissibility and reduction in are needed to better understand the duration of neutralisation by antibodies produced by COVID-19 vaccine induced-immunity. Since previous infection or vaccination in varying infection-induced immunity can offer >8 months degrees. Currently, no variant strains belong to of immunity according to existing data,31 some VOHC. The discovery of VOHC must be notified researchers infer that vaccine-induced immunity to WHO, reported to CDC and requires specific may last up to a year. In the event of waning treatment and prevention strategies.50 immunity post-vaccination, revaccination may Studies have shown a reduction in the be necessary for maintaining a substantial immune response against various variant strains proportion of the population to be immune to in vaccinated individuals. For example, B.1.351 the disease. (Beta variant) was shown to be 10.3–12.4- fold more resistant to neutralisation by sera 4.5 Infection after vaccination of vaccinated individuals and 9.4-fold more A small portion of the vaccinated population resistant to neutralisation by convalescent gets infected after COVID-19 vaccination. plasma of individuals who have recovered These individuals are referred to as vaccine from COVID-19. However, B.1.1.7(Alpha breakthrough cases. According to the Centre variant) was not shown to be more resistant to for Disease Control and Prevention (CDC), neutralisation by either convalescent plasma or as of 14th June 2021, > 139 million people in sera of vaccinated individuals.51 Another study the United States have been fully vaccinated reported that the escape of B.1.351 from natural and there were 3,729 breakthrough cases that and vaccine-induced immunity was largely ended up hospitalised (n=3,538, 95%) or dead related to E484K mutation, and to a lesser extent, (n=671, 18%).48 If a vaccinated person comes into K417N and N501Y mutations.52 close contact with an infected individual before In one study, the efficacy of the ChAdOx1 sufficiency immunity develops, breakthrough nCoV-19 vaccine (or AZD1222) against B.1.351 infection can occur and he or she is still capable was investigated. In the primary end-point of transmitting the disease.49 In addition, the analysis, the efficacy was observed to be 21.9% emergence of variant strains of SARS-CoV-2 for mild-to-moderate COVID-19, whereas an may allow breakthrough infection as not all efficacy of 10.4% in the secondary end-point variant strains are completely covered by all analysis was observed, suggesting that two doses vaccines. However, it is noteworthy that when of the vaccine did not show protection in mild-to- infection occurs in vaccinated individuals, they moderate COVID-19 caused by B1.1.351.53 With may be asymptomatic or presenting with milder the surge of COVID-19 cases caused by the Delta symptoms. variant, another study was conducted in the UK to compare the vaccine-induce immune response 4.6 Variant strains of SARS-CoV-2 by BNT162b2 (Pfizer/BioNTech vaccine) against Variant strains of SARS-CoV-2 have been three VOCs (Delta, Beta and Alpha variants) with detected in different parts of the world. The the original strain (Wildtype). Results showed emergence of variants will inevitably have an that when compared with the Wildtype, there impact on herd immunity. The CDC has classified was a 5.8-fold, 4.9-fold and 2.6-fold reduction variant strains into three categories: 1) variant in neutralising antibodies for the Delta, Beta and of interest (VOI), 2) (VOC) Alpha variants respectively.54 and 3) variant of high consequence (VOHC). The variants B.1.525 (Eta), B1.526 (Iota), 5. Can herd immunity against COVID-19 be B1.526.1, B.1.617, B1.617.1 (Kappa), B1.617.3 achieved? and P.2 (Zeta) belong to VOI, which have a Some experts such as Dr potential impact on treatment and potentially referred achieving herd immunity against reduced neutralisation by antibodies produced COVID-19 as “elusive” and “mystical” in one during previous infection or vaccination. B1.1.7 of his interviews,55 as we cannot be sure what (Alpha, first detected in the UK), P.1 (Gamma, metrics we should use to plan our way out of

212 COVID-19 VACCINE AND IMMUNITY the pandemic. Should it be the vaccination rates? reported (4 infections/ 10,000 person-days) >7

Should the R0, number of hospitalisations or days after second dose of BNT162b2. Among deaths be used instead? While no one can give the infected participants, a lower percentage of a definite answer, this does not mean vaccination vaccinated individuals had typical COVID-19 is not important. In fact, Dr Fauci went on to symptoms when compared with the unvaccinated say “We need to get away from waiting for individuals (36% vs 56%), while the percentage this mystical elusive number and just … get as of asymptomatic individuals was higher in the many people as we possibly can get vaccinated former than the latter (19% vs 14%), suggesting as quickly as possible.”55 that vaccinated individuals were less likely to Despite the many obstacles and unanswered have typical symptoms and more likely to be questions, we should still encourage people to asymptomatic in breakthrough cases.58 get vaccinated because research has shown that In a nutshell, current pieces of evidence COVID-19 vaccines do help in reducing the suggest that it is unlikely we will achieve full risk of severe disease. With billions of people herd immunity or eradicate SARS-CoV-2. Instead getting vaccinated globally, researchers now of aiming for full herd immunity, a practical kind have some real-world data on the effectiveness of herd immunity should be the target, in which of vaccines, on top of earlier data obtained from we can live a near-normal life without having the clinical trials. For example, Thompson et al massive and prolonged lockdowns.59 Similar reported the effectiveness of BNT162b2 (Pfizer/ to the influenza virus, SARS-CoV-2 is likely BioNTech vaccine) and mRNA 1273 (Moderna to linger and become a seasonal infection, but vaccine) in real-world conditions among frontline with lower hospitalisation and death rates due to workers with adjusted vaccine effectiveness of protection offered by the vaccines.60 In a Nature 91% and 81% for individuals who were fully survey involving 119 experts (immunologists, vaccinated and partially vaccinated, respectively. virologists and infectious disease researchers) Compared to unvaccinated individuals, those from 23 countries, 89% of them felt that it who contracted SARS-CoV-2 infection after full is highly likely or likely for SARS-CoV-2 to or partial vaccination had a viral load that was become endemic, while more than one-third of 40% lower, with 2.3 fewer days in the sickbed them felt that it is possible to eliminate the virus and a 58% lower risk of febrile symptoms. Thus, in some regions, with pockets of infections in findings of the study suggest that vaccination is others, which can be controlled quickly if enough associated with less severe disease evidenced by people had been vaccinated.61 Therefore, people a reduced viral load, shorter disease duration and should fear the disease rather than the vaccines, reduced febrile symptom risk.56 as the benefits of the vaccines far outweigh the In another real-world study with 86,601 risks and vaccination plays an important role if vaccinated subjects matched to an equal number we were to achieve this kind of “practical herd of unvaccinated controls, it was reported that immunity”. during the follow-up period after 7 days of 2nd dose BNT162b2 vaccine, high effective rates for 6. Future strategies a wide-range of outcomes were observed. These When experts were asked what they thought include 92% for documented infections, 94% for would be the biggest factors driving the symptomatic illness, 87% for hospitalisation and circulation of SARS-CoV-2 infection if it were 92% for severe disease. Such real-world data to become endemic, the top three factors were suggests that vaccination helps in reducing the immune escape, waning immunity and uneven risk of infection and severe disease.57 vaccine distribution.61 With these factors and the Hall et al., on the other hand, reported the current challenges in focus, this section discusses findings of another real-world study that enrolled some future strategies that may be beneficial as 8,203 vaccinated and 15,121 unvaccinated we continue our battle against COVID-19. healthcare workers in the United Kingdom. A higher number of infections/10,000 person- 6.1 Intensify vaccination efforts worldwide days was observed in the unvaccinated group In a global pandemic, a world effort is needed (n=977, 14 infections/10,000 person-days) to bring it to a halt because “no one is safe when compared to the vaccinated group. until everyone is safe”. Therefore, intensifying In the latter, 71 infections were reported (8 vaccination programs worldwide is extremely infections/10,000 person-days) >21 days after crucial. It is important that low-income and first dose of BNT162b2 and 9 infections were middle-income countries get sufficient vaccines

213 Malays J Pathol August 2021 to administer to their populations. On the predicting the variants that will be circulating other hand, high-income countries should join during a particular season is very much needed. countries like China, Russia and the US in recognising the importance of a vaccine patent 6.5 Continue the quest for curative treatment waiver, as all will eventually benefit if vaccines To this end, there is not a curative treatment for can be manufactured and distributed evenly COVID-19. Previous clinical trials on various worldwide.62 drugs have not produced promising results and most therapeutic options for COVID-19 are 6.2 Genomic surveillance of variants mainly symptomatic or supportive. However, Since the emergence of COVID-19, numerous this does not mean all efforts in the quest for variant strains have been identified, whereas curative treatment should stop. On the contrary, monitoring of variants plays a vital role in the development of drugs to treat COVID-19 infectious disease control. Genomic surveillance should be more vigorous than ever. Learning of current and new SARS-CoV-2 variants from the experience of other infectious diseases gives us more information concerning how the like HIV and hepatitis C, pharmacotherapy still virus evolves and the likely path it will take in plays an important role even though there is no the future. It will also alarm researchers and vaccine for these diseases. Hence, future research healthcare professionals if a particular variant on drugs to treat COVID-19 should go on while is likely to cause surges of COVID-19 cases the global vaccination campaigns continue to in certain regions. Successful surveillance play their role in this pandemic. networks require sequencing and sharing of adequate genomes to trace mutations.63 CONCLUSION Moreover, the efforts in the development of good Vaccine development for COVID-19 has surveillance networks are helpful in navigating progressed at extraordinary speed for the past one the development of next-generation vaccines. year, something which was not possible before the COVID-19 pandemic. Given the urgency of 6.3 Vaccine boosters the current situation, several research teams have If waning vaccine immunity were to occur and reported the efficacy of their vaccines in Phase full herd immunity could not be achieved, it III clinical trials in less than a year, whereas is likely that vaccine boosters are required to various vaccines have obtained authorisation prevent future surges especially during winter. for emergency use in many countries. While the In fact, experts believe that annual vaccination data appear promising, much is still unknown is likely, very much like the annual vaccination concerning the long-term protective- and adverse for influenza. However, it is not sure for how effects of these vaccines. many years vaccine boosters need to be given Although determination of the herd immunity to attenuate the surges of COVID-19 cases.64 threshold for SARS-CoV-2 can be done mathematically, many factors need to be taken 6.4 Next-generation vaccines into consideration. The reproductive number, Modifying vaccines to accommodate the preventive measures implemented and human changing virus is not something uncommon. behaviours can all influence the achievement of For example, the composition of the flu vaccine herd immunity which makes it an elusive concept. is reviewed before each flu season. Data Having said that, to achieve herd immunity by from genomic surveillance is updated in the natural infection is ludicrous and vaccination is World Health Organization Global Influenza a practical way forward. The global vaccination Surveillance and Response System, whereas the campaigns are ongoing in many countries and virus strains that are likely to be circulating in vaccines have been administered at exponential the community are selected to be the targets of speed. Nevertheless, many hurdles remain in the the seasonal flu vaccine.65 Like the quadrivalent battle against SARS-CoV-2 infection worldwide. flu vaccine which has been shown to prevent Among these challenges include the unequal illness and reduce healthcare utilisation,66 next- distribution of vaccines and vaccine hesitancy. generation COVID-19 vaccines can be designed Furthermore, with the emergence of new SARS- to target more than one strain of SARS-CoV-2, CoV-2 variants,50 it is unsure if the currently particularly the VOCs. However, good genomic available vaccines would be sufficient to control surveillance is the key for this strategy to work the pandemic. well, and a robust model in evaluating and

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New variant strains are of significance because coronaviruse/risk-comms-updates/update37- they not only contribute to immune escape, vaccine-development.pdf?sfvrsn=2581e994_6 reduction in vaccine efficacy and breakthrough 7. Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. infections, more importantly, they should be Biostatistics. 2019; 20(2):273-286. the research focus for the next-generation 8. Callaway E. The race for coronavirus vaccines: a vaccines, where various variant strains can be graphical guide. Nature. 2020 ;580(7805):576-577. targeted to prevent surges in COVID-19 cases 9. Chugh T. Timelines of COVID-19 vaccines. Curr post-vaccination. Meanwhile, monitoring of Med Res Pract.;10(4):137-138. the long-term efficacy and adverse effects of 10. Dong Y, Dai T, Wei Y, et al. A systematic review of existing vaccines and genomic surveillance of SARS-CoV-2 vaccine candidates. Signal Transduct Target Ther. 2020;5(1):237. variants should also be emphasised. Some experts 11. Khuroo MS, Khuroo M, Khuroo MS, Sofi AA, believe that SARS-CoV-2 is likely to stay for Khuroo NS. COVID-19 Vaccines: A Race Against years. Nonetheless, even if full herd immunity Time in the Middle of Death and Devastation! J and disease eradication are hard to achieve, a Clin Exp Hepatol. 2020;10(6):610-621. “practical herd immunity” is possible with low 12. Polack FP, Thomas SJ, Kitchin N, et al. Safety levels of mild infection and a near-normal life and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020;383(27):2603-2615. owing to sufficient vaccine-induced immunity 13. Baden LR, El Sahly HM, Essink B, et al. Efficacy that relieves the strains on the healthcare system. and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021; 384(5):403-416. Author’s contribution: The author alone is 14. Voysey M, Clemens SAC, Madhi SA, et al. 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