AN OVERVIEW OF AETIOPATHOGENESIS AND PREVENTION OF INFECTIOUS CANCERS

AN OVERVIEW OF AETIOPATHOGENESIS AND PREVENTION OF INFECTIOUS CANCERS

Mandeep Kaur, Rahul Sandhu, Priya Datta and Varsha Gupta *

Department of Microbiology, Government Medical College Hospital, Chandigarh, India.

ABSTRACT: Currently, the knowledge on the oncogenic behaviour exhibited by microbial agents is the result of long and laborious studies conducted over the years. It started with the liver fluke infection associated with bile duct carcinoma and bilharziasis with bladder cancer. Following this, multiple pathogens got implicated in carcinogenesis, including bacteria, many viruses, and even fungi. For some of these infections, the cancer-causal association has confirmatory evidence, but the data is limited for others. There is a need to understand the pathogenesis of these infectious cancers and the oncogenic mechanism of newly implicated infectious agents being added to the list of infectious cancer. Cancers arising out of infections are theoretically preventable either by vaccination or early treatment and careful drafting of public health policies can help to reduce the cancer burden. The concept of herd immunity in cancer prevention is new and emerging, but as it has an established role in preventing some infectious diseases, the same advantage can be conferred in the prevention of infectious cancers. Cancer research has a huge potential when it comes to cancer prevention, and the role of vaccination and herd immunity needs to be explored further.

Keywords: Infection, Cancer, Prevention, Vaccination, Herd Immunity

INTRODUCTION: During the end of 19^th century, for the very first time the parasitic infections, especially liver flukes and Schistosoma infections, were reported to cause cancers. This potential link between liver fluke’s infection with liver cancer and chronic bilharziasis with bladder cancer was established by Askanazy and Goebel, respectively ¹.

Rous in 1911 was credited with the demonstration of infectious origin of chicken sarcoma, but it took further 50 additional years before evidence for a causal association of infections with human cancers emerged ^{1, 2}.

The causative role of Epstein Barr virus (EBV) infection in Burkitt’s lymphoma, hepatitis B virus (HBV) in hepatocellular carcinoma (HCC) and human papillomavirus (HPV) in carcinoma cervix was also studied. Most of these infections have human to a human mode of transmission and spread very easily. Thus, it can be inferred that the cancers associated with such infections are also transmissible and can be labelled as ‘Infectious cancers’.

The global burden of infectious cancers was 17.8% and 16.1% of the total cancer burden in the year 2002 and 2008 respectively ³. The human carcinogens, including biological agents, have been classified under different categories depending upon their oncogenic potential by International Agency for Research on Cancer (IARC), a working group of cancer research Table 1. A total of 17 microbes that include 12.1% viruses, 5.6% bacteria, and 0.1% helminths have been placed under different groups ^{1, 4}. Helicobacter pylori, HPV, HBV, and Hepatitis C virus (HCV) contribute maximally to the total cancer burden caused by the infectious agents, thus making the gastric, liver, and cervical cancers as the commonest amongst the list of infectious cancers ^{3, 5}. The annual prevalence of infectious cancers in underdeveloped nations is about 1.5 million. The reason for such high occurrence could be explained by a high prevalence of infections in this part of the world ¹. Secondly, overcrowding, poor hygiene, reuse of medical devices, drug abuse, and lack of access to medical care are other factors that predispose to one or other infections possessing carcinogenic potential ⁶.

TABLE 1: GROUP CLASSIFICATION OF HUMAN CARCINOGENS ¹

FIG. 1: SHOWS THE MECHANISM OF INFECTIOUS CARCINOGENESIS

Cancer Pathophysiology and Pathogenesis of Infectious Cancers: Cancer is a condition of abnormal and uncontrolled growth of cells accompanied with tissue invasion. Genetic and epigenetic alterations can cause a normal cell to be transformed into abnormal cells (also known AS cancer cells) with changed gene expression and host signalling pathways ⁷. The changes associated with cancer occur at the three non-exclusive levels: (a) physiological level, which is related to a modification in the physiology of cells, tissues, and organs, (b) cellular level, that is, the alterations in the signalling pathways involved in critical cellular processes resulting in increased cancer risk, and (c) molecular level, that includes changes in key cellular structures at the molecular level such as genotoxicity ¹. Neoplastic transformation can occur due to hormones, drugs, infectious agents, chemicals, physical or mechanical trauma, or chronic irritations ⁸. A variety of infectious agents show persistence in the host population, which is thought to be the main mechanism involved in the carcinogenic process. Their removal from the host may sometimes reverse the tumor process confirming their carcinogenic role ². The three important mechanisms by which an infection can initiate or promote carcinogenesis are depicted in Fig. 1.

Infectious Cancer Agents: Mostly viruses, few parasites and one bacterial infection have proven role in cancer occurrence. Fungi have shown no proven cancer association, though such infections commonly occur during the course of cancer. The list of microorganisms showing causal association with cancers is discussed in Table 2.

TABLE 2: CLASSIFIED INFECTIOUS AGENTS AND THEIR ASSOCIATED CANCERS ^{5, 63}

 TABLE 3: MICROORGANISMS WITH POSSIBLE ONCOGENIC POTENTIAL

Viruses: Globally, approximately 12% of human infectious cancers are viral in origin, and more than 80% of them occur in developing countries. Despite their high prevalence, public health importance, and availability of suitable immunoprophylaxis, still the control, prevention and treatment of such virus-induced cancers face formidable challenges ⁹.

Hepatitis B and C Virus: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, causing one-third of cancer-related deaths globally. Chronic viral hepatitis caused by HBV and HCV is the major cause of HCC. An age-adjusted worldwide incidence of HCC is 10.1 per 1 lakh person-years, and hepatitis B, and hepatitis C collectively resulted in 4.9% of worldwide cancers in 2007.In 2018, the death toll of HCC was 810,000 persons, and the attributable fractions of HCC due to HBV and HCV were 33% and 21%, respectively ^{10, 11}.

HBV, a small, partially double-stranded DNA virus, is a major contributor to chronic liver disease. The virus persists in the hepatocyte nuclei and results in immune-mediated hepatic inflammation and injury. The persistent and chronic hepatic inflammation may induce mutagenic changes by viral integration into the host genome, thereby altering cellular gene expression or certain HBV proteins can directly cause malignant transformation ¹⁰.

The HBV prevalence varies among geographical regions, with the highest chronic infection rates reported from sub-Saharan Africa and East Asia. High rates in the Amazon and southern parts of eastern and central Europe and moderately affected regions with 2-5% prevalence are Middle East Indian subcontinent. Western European and North American countries report less than 1% chronic infection in the population ¹⁰.

HCV, a single-stranded (ss) RNA virus from family flaviviridae is transmitted via parenteral routes, intravenous drug abuse or by invasive sexual practices. Rarely mother to child transmission is reported. The estimated global prevalence of HCV infections are around 140 million infections. High mutation rate and prevalence of heterogenous but closely related quasi-species in HCV is due to the high replication rates and the lack of proof-reading capacity of the HCV-encoded polymerase ¹².

The viral replication and other pro-oncogenic events occur in the cytoplasm of hepatocytes, but the mechanism by which it damages host cell DNA to initiate oncogenesis is still unknown. The persistent HCV infection leads to chronic inflammation, fibrosis, steatosis, and oxidative DNA damage, thus can promote carcinogenesis. Secondly, HCV proteins like core protein, E1/E2 glycoproteins, p7, NS2, NS3, NS4, and NS5 can have direct oncogenic effects and/or upregulate the mitogenic processes. HCV prevalence is varied and depends on demographic factors, with most affected regions being Central and East Asia and North Africa while approximately 1.6% in the USA, less than 0.5% in Northern Europe, and up to 3% in rural regions of Romania ¹².

Major difference between HBV and HCV remains that currently no anti-HCV vaccine is available due to genetic variability exhibited by this RNA virus that acts as a major hurdle in the development of an effective vaccine ¹³. Recently, effective antiviral agents have become available for the treatment of HCV infection and thus prevention of cancer. NS3-4A protease inhibitors (directly acting anti- hepatitis C agents) telaprevir, simeprevir, parita-previr and boceprevir, in combination with PEG IFNα (pegylated interferon α) and ribavirin have been approved for treatment of HCV infection and have resulted in elimination of virus from blood especially in infections by HCV-1 genotype.^14,15

Epstein-Barr Virus: Infectious mononucleosis caused by Epstein-Barr virus, is a worldwide infection and tends to occur more in children aged 3-4 years in developing countries and among adolescent children in developed nations ¹⁶. Oropharynx is the primary site of infection, but the virus is capable of infecting B cells in addition to epithelial cells and frequently exhibits switching between the two sites. EBV has shown a causal relationship with a number of malignancies, namely B and T cell lymphomas, Hodgkin’s disease, post-transplant lymphoproliferative disease, leiomyo-sarcomas, nasopharyngeal and gastric carcinomas ¹⁷. The binding of major viral glycoproteins gp350/220 to the CD21 receptor on B cells causes cell transformation and establishes latent infection. During the latency period, EBV latent membrane proteins 1 and 2 affect the cellular gene expression and cell growth through anti-apoptotic mechanisms further contributing to cancer development ¹⁷.

Nasopharyngeal carcinoma, is maximally reported from South China, Singapore and Malaysia and also from a certain population group in North Africa, Alaska and Canada ¹⁸. For Burkitt’s lymphoma, Papua New Guinea and sub-Saharan Africa are seen as the endemic areas where 95% of its occurrence has been attributed to EBV infection. Burkitt’s lymphoma is the most common childhood malignancy in the central part of Africa, where EBV and malaria are considered cofactors in its carcinogenesis. In endemic areas, 95% of children get infected by 3 years of age, compared to the United States, where the infection is usually delayed until adolescence ¹⁹.

Standard therapy for EBV-associated carcinomas consists of multi-agent chemotherapy, radiation therapy combined with surgery of the cancers associated with EBV infection, Burkitt’s lymphoma, post-transplant lymphoproliferative disease and leiomyosarcomas are frequently seen among immunodeficient individuals suggesting the role of immunosurveillance in cancer prevention. Hence, the immune-therapy for EBV-associated tumours has been the target of research, and the work centered on adoptive transfer of EBV-specific cytotoxic T-cells has shown success, but the obstacles such as potential graft vs. host disease and resistance due to mutation of selected EBV epitopes need to be overcome. Vaccines capable of preventing primary EBV infection or boosting immune responses against EBV-associated tumours are under investigation ²⁰.

Human Herpes Virus 8/ Kaposi Sarcoma Herpes Virus (KSHV): The HHV-8 or KSHV is a lymphotropic virus that has a predilection for epithelial cells such as skin, blood vessels, and organs (commonly lung and gastrointestinal tract) where it undergoes lytic replication and has a tendency to establish latent infections for a lifetime. After its first description in 1872 as a rare hemangiosarcoma-like tumor in elderly men, Kaposi’s sarcoma is now regarded as an AIDS-defining condition with HHV-8 as the causative agent in 95% of the cases regardless of the HIV/AIDS status ²¹.

KS is a type of malignancy characterized by skin lesions that pass through patchy, plaque, and nodular stages, mostly appearing on extremities. In advanced stages, systemic involvement of lung and GIT often leads to fatal outcome.²¹Similar to EBV, HHV-8 infects B cells predominantly, but unlike EBV, lytic cycle is embraced rather than repressed ¹⁴. Viral genes, micro RNAs, and modulation of cellular immunity result in increased cell survival while viral, and host cytokines promote cell proliferation, angiogenesis, and enhances viral spread, thus promote the occurrence of Kaposi sarcoma ^{5, 20}.

Apart from KS, HHV-8 infection has been implicated in primary effusion lymphoma, which is a rare form of B cell non-Hodgkin lymphoma comprise less than 2% of HIV-1 related lymphomas, and Castleman’s disease (polyclonal lymphoproliferative disease), which itself is a non-cancerous condition, but on rare occasions can progress to cause plasmablastic lymphoma ^{1, 3, 5}. In high prevalence areas, HHV-8 infection is acquired during childhood (between 6-10 years), usually from within the family, and sometimes can progress to cause cancer later in life. In USA, Europe, and Australia, KSHV is seen more among HIV-1 positive homosexual men, and this finding was supported by a strong decline observed in KS incidence following the introduction of highly active antiretroviral therapy (HAART) for HIV treatment ²².

The therapeutic options to treat KS, PEL and MCD include surgery, radiation, and chemotherapy depending upon the disease stage. Ganciclovir/ valganciclovir, foscarnet/ cidofovir, and valacyclovir/ famciclovir combinations have been shown to treat HHV-8 associated diseases and may also prevent the formation of KS ^{21, 22}.

Human papillomavirus: Human papillomavirus, a member of papovaviridae family, is a small non-enveloped double stranded (ds) DNA virus and 50-60 nm in diameter ^{5, 20}. The genome of HPV consists of cDNA encoding sequences for six early (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2). Early proteins E1 and E2 are needed for replication and translation of virus, E2 additionally controls E6 and E7 expression while E4 and E5 help in viral assembly and growth stimulation. The late proteins L1 and L2 form minor and major capsid proteins ²³. The viral genome has three functional regions; first is a noncoding upstream regulatory region (URR), that regulates DNA replication, second is an “early” region, containing genes E1-E8 that are involved in viral replication and oncogenesis, and third is the “late” region, which encodes the viral capsid proteins (L1 and L2 structural proteins). Expression of the early gene products determines whether an HPV infection will be active or latent or will lead to malignant transformation ^{1, 24}.

HPVs are restricted in their host range to humans and primarily infect stratified epithelia at either cutaneous or mucosal sites. Genital HPVs infect primarily the cervix, vagina, vulva, penis, and anus. They are divided into high-risk types [16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 70] which are associated with anogenital cancer and low-risk types [6, 11, 42, 43, 44] that are associated with benign anogenital warts. Among low-risk types, HPV types 6 and 11 are responsible for 90% of all genital warts and can also cause recurrent respiratory papillomatosis, a disease in which benign tumours can grow leading from the nose and mouth into the lungs ^{25, 26}. Among the anogenital cancers, cervical cancer has received the most attention, and in 90% of cases, HPV types 16, 18, 31, 45 are implicated. Other conditions associated with high-risk HPV types include carcinoma of the vagina, vulva, penis and anus and their precancerous lesions ²⁷.

Sexually transmitted HPV infection is the most important risk factor for cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. Unlike many other cancers, cervical cancer occurs and strikes early during the reproductive period of a woman's life. Incidence usually rises in 30-34 years of age and peaks at 55-65 years, with a median age of 38 years (21-67 years). Worldwide, the annual incidence of cervical cancer is approximately 510,000 new cases and approximately 288,000 deaths. In US and Europe, half of the cervical cancer cases are associated with HPV-16 ^{24, 27}.

As per the Centers for Disease Control (CDC) estimates, more than 90% of sexually active men and 80% of women will get the infection with at least one type of HPV at any point in their lives ²⁷. AIDS patients, renal transplant patients receiving immunosuppressive therapy, and individuals with T cell deficiencies have increased rates of HPV persistence, anogenital lesions, and cervical cancer. Hence, the advent of a vaccine against HPV has stirred much excitement but much debate as well ²⁸.

Human T Lymphotropic Virus-1: HTLV-1 (ssRNA), a slow transforming retrovirus, is associated with adult T-cell leukemia. Like other retroviruses, it has adiploid genome with two long terminal repeats (LTRs) and bearsgag, pol, and env genes in addition to other accessory genes. HTLV-1 is transmitted through infected blood and blood products, sexual route, and mother to child via breastfeeding ⁵. The virus displays a special tropism for CD4 cells, the clonal proliferation of which may lead to adult T cell leukaemia (ATLL). Certain viral proteins like HTLV-1 Tax and HBZ proteins may activate viral transcription and modify the infected cell growth and division, eventually leading to cause cancer ²⁹. Though the virus has a very long latent period of 20 to 30 years, but once the tumour formation sets in, there occurs rapid progression of the disease. Infected children particularly are at higher risk of developing ATLL later in life. Relapses are common even after adequate chemotherapy, and the median survival in affected individuals is just eight months ^{5, 19}. Approximately 10 million people around the world are infected by HTLV-1, but the disease is manifested only in 2-5% of the infected individuals ²⁹.

The endemic areas for HTLV-1 infection are South-West Japan, the Caribbean countries, and parts of Africa and South America, with about 10% population infected with this virus. ATLL occurs exclusively in endemic areas with a cumulative incidence of 1-5% ⁵. An effective preventive strategy for HTLV-1 infection is screening blood donors, and many countries in endemic areas have implemented systematic screening programs for blood donors ³⁰. New targets in the therapies like peptides, recombinant protein, DNA and viral vectors that can generate neutralizing antibodies against the virus and confer multivalent cytotoxic T cell response against Tax gene need to be studied ³¹.

Parasites: The contribution of parasitic worms in human cancers was initially suspected based on the occurrence of a particular infection and cancer in the same geographical setting ³. Later on, the causal involvement of parasitic agents in cancers was documented in many studies. IARC (2011) has classified parasitic agents like S. haematobium, C. sinensis and O. viverrini in carcinogen group 1, S. japonicum in group 2B, and S. mansoni and O. felineus were assigned group carcinogen 3 depending upon their carcinogenic potential ¹.

Schistosomes: Schistosomes are blood dwelling parasitic flukes that belong to genus Schistosoma and family Schistosomatidae. It has six human pathogenic species namely S. haematobium, S. mansoni, S. japonicum, S. mekongi, S. interacalatum and S. guineesis that mainly differ from each other with respect to the final location in the host ¹.

Schistosomiasis is the second most common human infection after malaria in tropical and subtropical regions. S. haematobium and S. mansoni together contribute 95% of this infection. S. haematobium infection is endemic in 53 countries of the Middle East and Africa, and in 2003 close to 200 million people got infected with S. haematobium, and 85% of them resided in sub-Saharan Africa ¹.

Schistosoma haematobium infection is associated with 5 times increased risk of squamous cell cancer (SCC) of the urinary bladder. Soluble egg antigen released from miracidia induces the proliferation, hyperplasia and metaplasia in the organ epithelium. Furthermore, nitrosamine produced from its urinary precursors, urinary stasis, and raised urinary beta-glucuronidase levels are the other risk factors implicated in carcinogenic processes ³². S. japonicum and S. mansoni have shown weak cancer association. In one study, S. japonicum, which is located in superior mesenteric veins, showed a strong association with rectal cancer, apart from earlier known associations with HCC and colonic cancer ³³.

Blood transfusions and parenteral treatment provided for S. mansoni infection can indirectly increase the risk of HBV and HCV infections and thus HCC. Moreover, the depressed cell-mediated immune response in active intestinal schistosomiasis can prolong the carrier state of HBV and HCV viruses, further increasing the risk of developing HCC in such patients ³.

Opisthorcis and Clonorchis: Opisthorchis and Clonorchis, belonging family Opisthorchidae are pathologically important food-borne trematodes. The hermaphrodite adult worms of these parasites lay bile-stained operculated ovoid eggs that are indistinguishable between the two species ³⁴. Both these flukes inhabit the human liver and cause hepatobiliary diseases, including bile duct cancer and sometimes HCC. Opisthorchis viverrini, O. felineus and C. sinensis are the important species implicated in these cancers ^{1, 3}. Opisthorchis viverrini, is a definite human carcinogen and in endemic a rear, it is twice more commonly associated with cholangiocarcinoma than HCC. Otherwise, in a non-endemic region, cholangiocarcinoma is a rare tumour. The mechanism by which these flukes result in cancer includes the hyperplasia of the bile duct epithelium due to chronic irritation. The other carcinogenic factors include endogenous carcinogen production, formation of DNA methylating enzymes via p450 enzyme activation. Lastly, the production of cytotoxic nitric oxide from L-arginine can result in DNA damage helping the carcinogenic process ³.

The incidence of O. viverrini infection in Northeast Thailand is 2.4 times more common among males than females and remains one of the leading causes of death in this area. This particular species is also prevalent in Northeastern states of India, whereas its counterpart, O. felineus is not found in India but is prevalent in the North West Siberian region. Clonorchiasis is a common infection in China, Hong Kong, The Republic of Korea, and Japan. It is also quite prevalent and reported among the immigrants coming to North America from China and Laos. The maximum prevalence for C. sinensis is seen in Busan (previously known as Pusan), a metropolitan city in South Korea, hence the increased risk of cholangio carcinoma in that region ^{35, 36}.

Bacterial Causes of Cancer: Bacteria do not generally show carcinogenic behavior except when factors like chronic inflammation and toxic bacterial metabolites have played a role in cancer occurrence. Till date, only H. pylori have shown a proven role in carcinogenesis by its propensity to cause chronic inflammation.

Helicobacter pylori: Worldwide, the fifth most common cancer is gastric cancer, with an estimated 952,000 cases and 723,000 deaths reported in the year 2012 ⁵. Approximately 50% of the world's population harbours this organism in their stomach. Helicobacter pylori, a gram-negative bacillus, survives the gastric acidity and lives in a neutral pH niche between the mucus layer of the stomach and the gastric epithelium but never shows tissue invasion. Despite its non-invasiveness, H. pylori infection is invariably associated with inflammation but once established, the bacterium and associated inflammation are thought to last for decades ³⁷. This chronic inflammation by producing mutagenic free radicals and N-nitroso compounds induces cell proliferation, thereby resulting in cancerous changes. It is the first bacterial cause of human cancer and has been classed into group 1 human carcinogens by IARC. Chronic superficial gastritis is a precursor lesion of gastric adeno-carcinoma and increases the cancer risk two folds while its progressive form, i.e., chronic atrophic gastritis, increases the risk more to 9 folds. Further atrophic changes result in in metaplastic trans-formation of gastric epithelium to the intestinal epithelium, and cancer ensues thereafter ^{38, 39}. The most convincing evidence implicating H. pylori as carcinogenic came from four nested case-control studies from Hawaii, California, Great Britain and Taiwan, and it was further observed that the infection usually causes tumours distal to the gastric cardia ⁴⁰. While H. pylorus is an easily curable infection with a short course of antibiotics, it is tempting to think about creating a vaccine for the prevention of gastric cancer ³⁷. An oral recombinant H. pylori vaccine in phase 3 clinical trial in children in China has documented efficacy and safety and a future option to reduce H. pylori infections ⁴¹. The mere persistence of a microbe can disturb the microbial harmony of that body part and is a significant risk factor involved in carcinogenesis. Many studies are being carried out worldwide to determine the oncogenic potential in other unclassified microbes. The number of microbes showing carcinogenic behaviour is increasing, but the cancer-causal association is still not established for most of them to label them as classified human carcinogens. The list of such unclassified microbe cancer associations with a brief mention of the possible carcinogenic mechanism is given in Table 4.

Prevention of Infectious Cancers: Cancer prevention is the practice of taking active measures to decrease cancer incidence and mortality and is dependent upon both individual efforts to improve lifestyle and seek preventive screening and socioeconomic or public policy related to cancer prevention. More than 75% of cancer deaths could be prevented by avoiding the risk factors involved, including prevention from cancer-associated infections. Infectious cancers are usually preventable, and their occurrences can be prevented if appropriate existing public health methods for infection prevention like vaccination, safe injection practices, and antimicrobial therapy are applied. The best prevention practice is avoidance of infectious exposure itself. Still, even if it occurs, prompt post-exposure management in the form of preformed antibodies or effective cell-mediated immune cells can confer protection ⁶.

Role of Vaccination in Cancer Prevention: Long before the immunization era had begun, infectious diseases were the major contributors to morbidity and mortality among the human population. The vaccine discovery, especially against these debilitating and sometimes fatal infections, has significantly brought down the burden of illness, death, and long-term disability in the population. Most of the research effort in the field of prevention of infectious cancer is in the line of harnessing body’s immune system for protection against them. Thus today, the focus has shifted more into the cancer-preventive strategies ⁴². Chronic inflammation due to persistent infection often plays a role in initiating the carcinogenic process like in HBV infection-causing HCC; HPV infection causing cervical cancer; EBV infection-causing nasopharyngeal cancer; and H. pylori infection leading to gastric cancer ^{1, 43}. The vaccines protect against infection by hampering the microbial process of causing damage to the body cells, but chronic infections can protect against the development of cancer ⁴². Till date, effective vaccines are available for only two viral infections (HBV and HPV) that may lead onto cancer. Much research work is underway for the development of vaccines against other oncogenic microbes such as H. pylori and EBV.

To curtail the carcinogenesis, therapies to eliminate the microbial agent from the blood are required, which is a difficult task in persistent viral infection, and till date, this mechanism of cancer control has achieved little success ⁴⁴.

Hepatitis B Vaccine: In areas endemic for HBV infection, liver cancer results from chronic HBV infection in approximately 60-90% of adults and almost 100% children ⁴⁴. Hence immunizing susceptible children at an early age becomes an important preventive measure. The first vaccine for HBV came in the early 1980s and was primarily started to target viral hepatitis. Later on, its preventive role in decreasing the occurrence of HCC was proved to be a major milestone in cancer prevention ¹⁹.

Hepatitis B surface antigen (HBsAg), also called ‘Australia antigen’ was first time used in 1971 for testing in blood banks. Later on, a heat-treated HBV vaccine based on HBsAg was developed in 1975. Improving upon this vaccine, in 1980stwo plasma-derived inactivated vaccines (known as “first-generation vaccines”) approved by the US Food and Drug Administration (FDA) came into existence and showed excellent efficacy ^{44, 45}. They were subunit vaccines containing 22-nm HBsAg particles made of plasma from chronic HBsAg carriers. The preparations underwent vigorous inactivation steps, purified, and aluminium hydroxide was added as an adjuvant. However, the concerns about human safety by using blood products led to its discontinuation after a genetically engineered DNA recombinant vaccine was introduced in 1990. This recombinant vaccine was a yeast-derived HBsAg vaccine (“second-generation vaccines”) that also showed excellent results and was much safer than first-generation vaccine. Although the current vaccines are highly effective(94-98% efficacy)and provide 20 years of protection from chronic HBV infection, certain population groups such as elderly, smokers, obese, chronic hepatic or chronic renal diseases patients don’t respond well to this vaccine ⁴⁶. Finally, the third generation vaccine was developed by recombinant DNA technology in mammalian cells using three components of the virus, i.e., HBsAg, pre-S1 and pre-S2 HBV proteins, and improved adjuvants more immunogenic ⁴⁵.

Currently, two different formulations of yeast-derived vaccines are in use worldwide. The vaccine should be kept at 2-8°C and never be frozen. It is heat stable and can be stored for one month at ambient temperature even in tropical areas, which increases the vaccine coverage to far-off areas where a refrigeration facility is not available ¹³.

The first dose of vaccine is recommended to be administered at birth, followed by three booster doses at 4 weeks intervals. The current dosing schedule has been observed to confer protection from chronic HBV-related hepatitis and HCC later in life ²⁰. This is the kind of the first vaccine that is given during infancy and eliminates the disease in adults ⁴⁶. Children born to mothers who are HBsAg positive should receive HBIG in addition to full HBV vaccination in order to protect them from the risk of chronic infection in case they have acquired infection from the mother ⁴⁷. Current HBV vaccination programme has certain limitations like multiple parenteral doses, high non-responder rate (10%), infection by escape mutants, and high cost of vaccination ¹⁹.

Newer pentavalent and hexavalent combination vaccines have addressed the issue of multiple doses and also have helped in increasing the vaccine coverage ¹³. Oral vaccines for HBV would be the best option that may obviate the need for the trained personnel required for parenteral administration of vaccines ¹⁹.

Human Papillomavirus Vaccine: Cervical cancer is the second most common cancer occurring in women worldwide. It is also one of the most common causes of cancer death in developing countries. Infection by high-risk types of HPV (16 and 18) contributes to more than 70% of all cervical cancer cases. Certain non-oncogenic HPV serotypes (6 and 11) are responsible for the occurrence of benign genital diseases such as genital warts in 85% of cases. Routine screening procedures being followed in developing countries like India are not of much use as the estimates suggest that more than 80% of sexually active women usually acquire genital HPV by 50 years of age. Cervical cancer strikes early in life; hence the preventive strategies should also start at an early age, long before the first sexual exposure ⁴⁸. The excellent antibody response and high levels among young children suggest that the best time to initiate the vaccine series is before the exposure to HPV infection. Moreover, the fact that HPV infection is acquired up to 6 times more likely at a younger age (<15 years) than the infection acquisition at an older age (>18 years) and post-infection to have a cancerous conclusion takes another 20 years, which makes vaccination of young children a high priority ^{43, 44}.

The vaccines for HPV are manufactured by recombinant DNA technology producing non-infectious virus-like particles (VLPs) comprising mainly HPV L1 protein. Three FDA-approved HPV vaccines, namely Gardasil, Gardasil 9, and Cervarix, are used in routine practice ⁴⁸. All three vaccines provide protection against HPV types 16 and 18, which are responsible for 70% of cases of cervical cancers, while Gardasil and Gardasil 9 provide additional protection against HPV types 6 and 11 infections. The vaccines don’t confer any protection against the HPV serotypes acquired before vaccination ^{43, 44}. Cervarix provides protection against cervical cancer only. It contains L1 proteins of HPV serotypes 16 and 18 and aluminium sulphate as an adjuvant. It has shown 90% efficacy in clinical trials with three doses given at 0, 1, and 6 months and is protective against type 16/18-related CIN-2/3 and AIS ^{43, 48}.

Gardasil contains L1 proteins from HPV 16, 18, 6, and 11 serotypes and in clinical trials reported from five continents, including Asia, has shown 100% efficacy against types 16/18-related CIN-2/3 and AIS. The three-dose regimen (0, 2, 6 months) in women aged 16-26 years protects from almost 100% vaginal, cervical, and vulval cancers and genital warts ^{43, 48}.

Gardasil 9 (HPV serotypes 6, 11, 16, 18, 31, 33, 45, 52, and 58), the newest vaccine, has shown 97% efficacy in providing protection against all HPV-associated cancers (except oropharyngeal cancer). It is approved to be used in people aged between 9-26 years ^{44, 48}.

Till date, none of the vaccines are currently approved to prevent oropharyngeal cancers, but it would not be surprising if future data prove that these cancers would also be prevented with current vaccination.

The vaccination schedule of HPV vaccines for special risk groups is as under: ^{48, 49}

1. In children and age group 9-14 years, 2 dose schedule is recommended at a gap of 6 months.
2. In immunocompromised persons and age group 15-26 years, 3 dose schedule (0, 4-8 weeks, and 6 months later) is recommended.

The dosage schedule differs with different types of vaccines like for Gardasil^TM three doses are recommended at 0, 2, and 6 months or at 0, 1, and 6 months while for Cervarix^TM (minimum interval of 4 weeks between the first and the second dose, 12 weeks between the second and third dose and 24 weeks between the first and third dose) is recommended. HPV vaccines don’t interfere with other vaccines; hence can be given simultaneously with other vaccines such as Hepatitis B and Tdap ⁴³. But certain barriers like the high cost of the vaccine, safety concerns, misperceptions that vaccine is required only in sexually active females but not in children, and the risk of promiscuity are the reasons for low HPV immunization rates.

The strategies like a reminder/recall systems; focused interventions targeting staff, clinicians, parents, assessment and feedback activities; and school-based HPV vaccination programs can help in increasing HPV vaccine coverage ⁴⁶.

HPV Vaccination in Males: The burden of HPV associated cancers in men is comparable to that among women in developed parts of the world such as those in Western Europe, but unlike women, there is no screening for anal cancer and oropharyngeal squamous cell carcinoma, the malignancies which are increasing in incidence particularly in men. Moreover, there is a difference in the level of humoral immune response against infection among the two genders.

While the majority of women ≥70% seroconvert after detectable cervical HPV infection with antibody to the major coat protein L1, in the case of men only ≥20–30% do so. Despite the poor antibody response in natural infection, 100% seroconversion has been observed in men post-vaccination. It is clear from all these facts that men will definitely benefit from HPV vaccination, still, only a few nations have included the recommendations for boys and men in their HPV immunization program ⁵⁰. Australia is the first country to approve the quadrivalent HPV vaccine use in men between age group 9 and 15 years, and in other developed nations, male vaccination is given between age group 9-26 years ³⁵. The protective efficacy of the quadrivalent vaccine in two studies against anal precancerous state and genital warts was observed as 75% and 90%, respectively ^{44, 51}. But to draw a proven conclusion about the vaccine efficacy in the male population, the results of the ongoing studies should be analyzed before introducing this vaccine for routine use in males, especially in developing nations ⁴⁴.

Role of Herd Immunity in Cancer Prevention: Herd immunity is the prevailing level of immunity in the population acquired by either vaccination or natural infection that helps in reducing the risk of infection spread among susceptible individuals. The term ‘herd immunity’ was defined and used for the first time in year 1923. During 1930s, the role of herd immunity in disease prevention was realized when a temporary decrease in the incidence of measles cases occurred following measles vaccination to a significant number of children in that area. Mass vaccination campaigns for disease prevention became very common and had achieved their goals of decreased infection transmission for many diseases ^52-54. The indirect benefits of vaccination to unvaccinated susceptible populations conferred by existing herd immunity and its importance were recognized in 1980 when this natural protection helped achieve the global eradication of smallpox ⁵⁵. Herd immunity acts in two ways for disease prevention; firstly, by breaking the chain of infection and secondly by reducing the source and total susceptible population ⁵⁶.

Herd Immunity in High-Risk Groups: Following infection or post-vaccination, the development of immunity in an individual is based on host, type of agent, and environmental factors. Immunodeficient individuals like people suffering from HIV/AIDS, haematological cancers, dysfunctional spleen, and those receiving chemotherapy and radiotherapy get the maximum benefit of herd immunity ^57-60.

A newborn whose immune system is not competent enough to fight against disease too is benefitted from prevailing herd immunity in the population ⁵⁹. Hence, among immune-deficient individuals rather than active vaccination, herd immunity plays an important role in the prevention against infectious diseases as they are unable to generate long-lasting immunity because of ineffective immune response to vaccine components ⁵³.

Role in Infectious Cancers: Herd immunity doesn’t confer protection for all infectious diseases. The infections that are easily transmissible from one person to another will be able to derive the benefit of herd immunity, e.g., contact and droplet infections. In sexually transmitted infections, the high level of immunity in one gender can result in induction of immunity in the sexual partners due to herd effect.

Hence, herd immunity plays an important role in the control of STIs. Theoretically, vaccinating all sexually active females can ultimately confer protection to the opposite sex against a particular infection, but this doesn’t hold true for homosexual men. Therefore, the vaccination of men also becomes necessary, especially when an effective herd immunity has to be established in a high-risk population ⁶¹. The role of herd immunity in an infectious cancer is possible only when the spread of underlying infection leading to cancer can be prevented. Only two infectious cancers till date are preventable by vaccine i.e. HCC by HBV vaccine and carcinoma cervix by the HPV vaccine. Though the effect of herd immunity has not been observed with hepatitis B vaccination, where individual vaccination provides only individual immunity, for HPV, the herd immunity can play an important role in prevention from disease and later on from its carcinogenic effect.

A meta-analytical study supported the fact that a significant reduction [OR of 0.14 (95%CI 0.09–0.21)] in the frequency of high-grade cervical lesion was observed among women post-vaccination ⁶². Although no indirect benefits of vaccination and herd effect were seen in the HPV vaccine field trials done in developed nations, in endemic regions, this highly effective vaccine can provide benefit to the susceptible unvaccinated and uninfected population against cervical cancers via herd immunity ⁵⁵.

CONCLUSION: Cancer development is the result of a series of genetic modifications induced by a wide variety of external factors, including infections. This list of infections associated with cancers is on the rise, but the convincing evidence for most of the associations is still missing and calls for more research.

Such infectious cancers are easily preventable if the infections are treated in time. Few of them are vaccine-preventable, and the vaccines warrant the protection against infections and indirectly against their carcinogenic complications.

The concept of herd immunity is emerging as far as cancer prevention is concerned and encouraging, too, for its role in decreasing the cancer burden. But the possible mechanisms involved in conferring cancer protection is a topic of continuing research.

DISCLOSURE STATEMENT: This is submitted that none of the authors has any conflict of interest.

FUNDING: This research received no specific grant from any funding agency in public, commercial or not-for-profit sectors.

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    Kaur M, Sandhu R, Datta P and Gupta V: An overview of aetiopathogenesis and prevention of infectious cancers. Int J Pharm Sci & Res 2021; 12(11): 5662-76. doi: 10.13040/IJPSR.0975-8232.12(11).5662-76.

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